Boron-containing small molecules

ABSTRACT

This invention provides novel compounds, methods of using the compounds, and pharmaceutical formulations comprising the compounds.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/507,453, filed Oct. 6, 2014, which is a continuation of U.S. patentapplication Ser. No. 13/678,576, filed Nov. 16, 2012, now U.S. Pat. No.8,853,186, which claims priority to U.S. Provisional Patent ApplicationNo. 61/562,373, filed on Nov. 21, 2011, the contents of which isincorporated by reference herein in its entirety.

Ectoparasites such as fleas, lice, flies, mosquitoes, ticks and mitesare problematic for man and animal alike. Such ectoparasites seriouslyimpact productivity in the domesticated animal industry by reducingweight gain, causing poor quality hide, wool, and meat, and in somecases resulting in death. Ectoparasites are also responsible, in part,for the spread of disease and discomfort in food and companion animals.Ectoparasites in particular are known to harbor and transmit a varietyof microbial pathogens, including bacteria, viruses and protozoanparasites, many of which are pathogenic to humans, other warm-bloodedmammals and birds. Diseases in which ectoparasites have been implicatedinclude, but are not limited to, malaria, scabies, rosacea, lymphatic-and blood-born filariasis, trachoma, trypanosomiasis, Leishmaniasis,Rocky Mountain Spotted Fever, Lyme Disease, babesiosis, and food-borneillnesses due to Salmonella, E. coli and Campylobacter, for example.

The medical importance of ectoparasiticide infestations has prompted thedevelopment of reagents capable of controlling such infestations.Commonly encountered methods to control ectoparasiticide infestations,for example, have generally focused on use of insecticides, which areoften unsuccessful or unsatisfactory for one or more of the followingreasons: (1) failure of owner or applicator compliance (frequentadministration is required); (2) behavioral or physiological intoleranceof the animal to the pesticide product or means of administration; (3)the emergence of ectoparasites resistant to the reagent; and (4)negative impact on the environment and/or toxicity.

Specifically, ticks parasitize wild as well as domesticated animals andhumans, and are known or suspected to be responsible for thetransmission of pathogens including bacteria, viruses and protozoanparasites. Currently, ticks are considered to be second in the world tomosquitoes as vectors of human diseases, but they are considered to bethe most important vector of pathogens in North America. Effectiveelimination of tick infestations is difficult and often impractical, dueto the need for concomitant treatment of the immediate host as well asthe environmental reservoir. Presently, tick control is effected byintegrated pest management in which different control methods areadapted to one area or against one tick species with due considerationto their environmental effects.

While the use of insecticides and pesticides have been beneficial,alternative or improved compounds, formulations, and methods are needed.Desirable compounds, formulations, and methods would not only providealternative therapies, but would also overcome at least some limitationsof current approaches. Such limitations include toxicity and safety ofboth the animal and the user/owner, limited efficacy (potency andduration), and resistance issues. Also impacting the beneficial use ofinsecticides and pesticides are administration obstacles, which includemode and recurrence of administration. For example, reducing thefrequency of administration while maintaining efficacy is desirable, asexcessive and repeated treatment of animals is often inconvenient and/ordifficult.

As used herein, the singular forms “a,” “an”, and “the” include pluralreferences unless the context clearly dictates otherwise. For example,reference to “an active agent” includes a single active agent as well astwo or more different active agents in combination. It is to beunderstood that present teaching is not limited to the specific dosageforms, pharmaceutically acceptable excipients, or the like, disclosedherein and as such may vary.

The abbreviations used herein generally have their conventional meaningwithin the chemical and biological arts.

The following abbreviations have been used: Ac is acetyl; AcOH is aceticacid; ACTBr is acetyltrimethylammonium bromide; AIBN isazobisisobutyronitrile or 2,2 azobisisobutyronitrile; aq. is aqueous; Aris aryl; B₂pin₂ is bis(pinacolato)diboron; Bn is, in general, benzyl[see Cbz for one example of an exception]; (BnS)₂ is benzyl disulfide;BnSH is benzyl thiol or benzyl mercaptan; BnBr is benzyl bromide; Boc istert-butoxy carbonyl; Boc₂O is di-tert-butyl dicarbonate; Bz is, ingeneral, benzoyl; BzOOH is benzoyl peroxide; Cbz or Z isbenzyloxycarbonyl or carboxybenzyl; Cs₂CO₃ is cesium carbonate; CSA iscamphor sulfonic acid; CTAB is cetyltrimethylammonium bromide; Cy iscyclohexyl; DABCO is 1,4-diazabicyclo[2.2.2]octane; DCM isdichloromethane or methylene chloride; DHP is dihydropyran; DIAD isdiisopropyl azodicarboxylate; DIEA or DIPEA isN,N-diisopropylethylamine; DMAP is 4-(dimethylamino)pyridine; DME is1,2-dimethoxyethane; DMF is N,N-dimethylformamide; DMSO isdimethylsulfoxide; EtOAc is ethyl acetate; EtOH is ethanol; Et₂O isdiethyl ether; EDCI is N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride; ELS is evaporative light scattering; equiv or eq isequivalent; h is hours; HATU isO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; HOBt is N-hydroxybenzotriazole; HCl is hydrochloricacid; HPLC is high pressure liquid chromatography; ISCO Companion isautomated flash chromatography equipment with fraction analysis by UVabsorption available from Presearch; KOAc or AcOK is potassium acetate;K₂CO₃ is potassium carbonate; LiAlH₄ or LAH is lithium aluminum hydride;LDA is lithium diisopropylamide; LHMDS is lithium bis(trimethylsilyl)amide; KHMDS is potassium bis(trimethylsilyl) amide; LiOH is lithiumhydroxide; m-CPBA is 3-chloroperoxybenzoic acid; MeCN or ACN is methylcyanide or cyanomethane or ethanenitrile or acetonitrile which are allnames for the same compound; MeOH is methanol; MgSO₄ is magnesiumsulfate; mins or min is minutes; Mp or MP is melting point; NaCNBH₃ issodium cyanoborohydride; NaOH is sodium hydroxide; Na₂SO₄ is sodiumsulfate; NBS is N-bromosuccinimide; NH₄Cl is ammonium chloride; NIS isN-iodosuccinimide; N₂ is nitrogen; NMM is N-methylmorpholine; n-BuLi isn-butyllithium; overnight is O/N; PdCl₂(pddf) is1,1′-Bis(diphenylphosphino) ferrocene]dichloropalladium(II); Pd/C is thecatalyst known as palladium on carbon; Pd₂(dba)₃ is an organometalliccatalyst known as tris(dibenzylideneacetone)dipalladium(O); Ra Ni orRaney Ni is Raney nickel; Ph is phenyl; PMB is p-methoxybenzyl; PrOH is1-propanol; iPrOH is 2-propanol; POCl₃ is phosphorus chloride oxide;PTSA is para-toluene sulfonic acid; Pyr. or Pyr or Py as used hereinmeans pyridine; RT or rt or r.t. is room temperature; sat. is saturated;Si-amine or Si—NH₂ is amino-functionalized silica, available fromSiliCycle; Si-pyr is pyridyl-functionalized silica, available fromSiliCycle; TEA or Et₃N is triethylamine; TFA is trifluoroacetic acid;Tf₂O is trifluoromethanesulfonic anhydride; THF is tetrahydrofuran; TFAAis trifluoroacetic anhydride; THP is tetrahydropyranyl; TMSI istrimethylsilyl iodide; H₂O is water; diNO₂PhSO₂Cl is dinitrophenylsulfonyl chloride; 3-F-4-NO₂-PhSO₂Cl is 3-fluoro-4-nitrophenylsulfonylchloride; 2-MeO-4-NO₂-PhSO₂Cl is 2-methoxy-4-nitrophenylsulfonylchloride; and (EtO)₂POCH₂COOEt is a triethylester of phosphonoaceticacid known as triethyl phosphonoacetate.

“Compound of the invention,” as used herein refers to the compoundsdiscussed herein, salts (e.g. pharmaceutically acceptable salts),prodrugs, solvates and hydrates of these compounds.

An “additional therapeutic agent” refers to a compound (or a salt, (e.g.pharmaceutically acceptable salt), prodrug, solvate and hydrate thereof)that is administered in combination with a compound of the invention orwith a compound described herein. In an exemplary embodiment, theadditional therapeutic agent exhibits activity against an ectoparasite,such as a tick and/or flea, and therefore has the potential to killand/or inhibit the growth of an ectoparasite. In an exemplaryembodiment, the additional therapeutic agent is a compound (or a salt,(e.g. pharmaceutically acceptable salt), prodrug, solvate and hydratethereof) described herein. In an exemplary embodiment, the additionaltherapeutic agent is a compound (or a salt, (e.g. pharmaceuticallyacceptable salt), prodrug, solvate and hydrate thereof) known in theart. An additional therapeutic agent can itself be formulated foradministration according to methods described herein or known in theart.

The term “poly” as used herein means at least 2. For example, apolyvalent metal ion is a metal ion having a valency of at least 2.

“Moiety” refers to a radical of a molecule that is attached to theremainder of the molecule.

The symbol

, whether utilized as a bond or displayed perpendicular to a bond,indicates the point at which the displayed moiety is attached to theremainder of the molecule.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals, having the number of carbon atoms designated (i.e. C₁-C₁₀means one to ten carbons). In some embodiments, the term “alkyl” means astraight or branched chain, or combinations thereof, which may be fullysaturated, mono- or polyunsaturated and can include di- and multivalentradicals. Examples of saturated hydrocarbon radicals include, but arenot limited to, groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl,cyclopropylmethyl, homologs and isomers of, for example, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group isone having one or more double bonds or triple bonds. Examples ofunsaturated alkyl groups include, but are not limited to, vinyl,2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thehigher homologs and isomers.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified, but notlimited, by —CH₂CH₂CH₂CH₂—. Typically, an alkyl (or alkylene) group willhave from 1 to 24 carbon atoms, with those groups having 10 or fewercarbon atoms being preferred in the invention. A “lower alkyl” or “loweralkylene” is a shorter chain alkyl or alkylene group, generally havingeight or fewer carbon atoms.

The term “alkenylene” by itself or as part of another substituent meansa divalent radical derived from an alkene.

The term “cycloalkylene” by itself or as part of another substituentmeans a divalent radical derived from a cycloalkyl.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical derived from an heteroalkane.

The term “heterocycloalkylene” by itself or as part of anothersubstituent means a divalent radical derived from an heterocycloalkane.

The term “arylene” by itself or as part of another substituent means adivalent radical derived from an aryl.

The term “heteroarylene” by itself or as part of another substituentmeans a divalent radical derived from heteroaryl.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and at least one heteroatom. In someembodiments, the term “heteroalkyl,” by itself or in combination withanother term, means a stable straight or branched chain, or combinationsthereof, consisting of the stated number of carbon atoms and at leastone heteroatom. In an exemplary embodiment, the heteroatoms can beselected from the group consisting of B, O, N and S, and wherein thenitrogen and sulfur atoms may optionally be oxidized and the nitrogenheteroatom may optionally be quaternized. The heteroatom(s) B, O, N andS may be placed at any interior position of the heteroalkyl group or atthe position at which the alkyl group is attached to the remainder ofthe molecule. Examples include, but are not limited to, —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, such as,for example, —CH₂—NH—OCH₃. Similarly, the term “heteroalkylene” byitself or as part of another substituent means a divalent radicalderived from heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is mean to include, but not be limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, substituent that can be a single ring or multiple rings(preferably from 1 or 2 or 3 rings), which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to four heteroatoms. In an exemplary embodiment, theheteroatom is selected from B, N, O, and S, wherein the nitrogen andsulfur atoms are optionally oxidized, and the nitrogen atom(s) areoptionally quaternized. A heteroaryl group can be attached to theremainder of the molecule through a heteroatom. Non-limiting examples ofaryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl,4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined herein. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridiylethyl and the like) including thosealkyl groups in which a carbon atom (e.g. a methylene group) has beenreplaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxyl)propyl, and the like).

For brevity, the term “heteroaryl” when used in combination with otherterms (e.g., heteroaryloxy, heteroarylthioxy, heteroarylalkyl) includesthose radicals in which a heteroaryl group is attached through the nextmoiety to the rest of the molecule. Thus, the term “heteroarylalkyl” ismeant to include those radicals in which a heteroaryl group is attachedto an alkyl group (e.g., pyridylmethyl and the like). The term“heteroaryloxy” is meant to include those radicals in which a heteroarylgroup is attached to an oxygen atom. The term “heteroaryloxyalkyl” ismeant to include those radicals in which an aryl group is attached to anoxygen atom which is then attached to an alkyl group. (e.g.,2-pyridyloxymethyl and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) are meant to include both substituted and unsubstitutedforms of the indicated radical. Preferred substituents for each type ofradical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) are generically referred to as “alkyl groupsubstituents,” and they can be one or more of a variety of groupsselected from, but not limited to: —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″,—SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″,—OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′,—NR″″″—C(NR′R″R′″)═NR″, —NR″—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —NR″SO₂R′, —CN, —NO₂, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, in a number ranging from zero to (2m′+1), wherem′ is the total number of carbon atoms in such radical. R′, R″, R′″, R″and R′ each preferably independently refer to hydrogen, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g., arylsubstituted with 1 or 2 or 3 halogens, substituted or unsubstitutedalkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When a compoundof the invention includes more than one R group, for example, each ofthe R groups is independently selected as are each R′, R″, R′″, R″″ andR′″″ groups when more than one of these groups is present. When R′ andR″ are attached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 5-, 6-, or 7-membered ring. For example, —NR′R″is meant to include, but not be limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are generically referredto as “aryl group substituents.” The substituents are selected from, forexample: —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen,—SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR″″″-C(NR′R″R′″)═NR″″,—NR″″—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NR″SO₂R′, —CN,—NO₂, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in anumber ranging from zero to the total number of open valences on thearomatic ring system; and where R′, R″, R′″, R″″ and R′″″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl and substituted or unsubstituted heteroaryl. When acompound of the invention includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R′″,R″″ and R′″″ groups when more than one of these groups is present.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CRR′)_(q)—U—, wherein T and U are independently —NR—, —O—,—CRR′— or a single bond, and q is an integer from 0 or 1 or 2 or 3.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A-(CH₂)_(r)—B—, wherein A and B are independently —CRR′—, —O—,—NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is aninteger from 1 or 2 or 3 or 4. One of the single bonds of the new ringso formed may optionally be replaced with a double bond. Alternatively,two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula—(CRR′)_(s)—X—(CR″R′″)_(d)—, where s and d are independently integersfrom 0 or 1 or 2 or 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″ and R′″ are preferablyindependently selected from hydrogen or substituted or unsubstituted (C₁or C₂ or C₃ or C₄ or C₅ or C₆)alkyl.

“Ring” as used herein, means a substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. A ringincludes fused ring moieties. The number of atoms in a ring is typicallydefined by the number of members in the ring. For example, a “5- to7-membered ring” means there are 5 or 6 or 7 atoms in the encirclingarrangement. Unless otherwise specified, the ring optionally includes aheteroatom. Thus, the term “5- to 7-membered ring” includes, for examplephenyl, pyridinyl and piperidinyl. The term “5- to 7-memberedheterocycloalkyl ring”, on the other hand, would include pyridinyl andpiperidinyl, but not phenyl. The term “ring” further includes a ringsystem comprising more than one “ring”, wherein each “ring” isindependently defined as above.

As used herein, the term “heteroatom” includes atoms other than carbon(C) and hydrogen (H). Examples include oxygen (O), nitrogen (N) sulfur(S), silicon (Si), and boron (B).

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitutionreaction, such as a nucleophilic substitution reaction. By way ofexample, representative leaving groups include triflate, chloro, bromoand iodo groups; sulfonic ester groups, such as mesylate, tosylate,brosylate, nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

The symbol “R” is a general abbreviation that represents a substituentgroup that is selected from substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted cycloalkyl and substituted or unsubstitutedheterocycloalkyl groups.

By “effective” amount of a drug, formulation, or permeant is meant asufficient amount of an active agent to provide the desired local orsystemic effect. A “Topically effective” or “therapeutically effective”amount refers to the amount of drug needed to effect the desiredtherapeutic result.

The term “pharmaceutically acceptable salt” is meant to include a saltof a compound of the invention which are prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds of the inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino (suchas choline or diethylamine or amino acids such as d-arginine,l-arginine, d-lysine, or l-lysine), or magnesium salt, or a similarsalt. When compounds of the invention contain relatively basicfunctionalities, acid addition salts can be obtained by contacting theneutral form of such compounds with a sufficient amount of the desiredacid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, and the like. Also included are salts of amino acidssuch as arginate and the like, and salts of organic acids likeglucuronic or galactunoric acids and the like (see, for example, Bergeet al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the invention contain bothbasic and acidic functionalities that allow the compounds to beconverted into either base or acid addition salts.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompounds in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the invention provides compounds which are ina prodrug form. Prodrugs of the compounds described herein readilyundergo chemical changes under physiological conditions to provide thecompounds of the invention. Additionally, prodrugs can be converted tothe compounds of the invention by chemical or biochemical methods in anex vivo environment.

Certain compounds of the invention can exist in unsolvated forms as wellas solvated forms, including hydrated forms. In general, the solvatedforms are equivalent to unsolvated forms and are encompassed within thescope of the invention. Certain compounds of the invention may exist inmultiple crystalline or amorphous forms.

Certain compounds of the invention possess asymmetric carbon atoms(optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers are encompassed within thescope of the invention. The graphic representations of racemic,ambiscalemic and scalemic or enantiomerically pure compounds used hereinare taken from Maehr, J. Chem. Ed. 1985, 62: 114-120. Solid and brokenwedges are used to denote the absolute configuration of a stereocenterunless otherwise noted. When the compounds described herein containolefinic double bonds or other centers of geometric asymmetry, andunless specified otherwise, it is intended that the compounds includeboth E and Z geometric isomers. Likewise, all tautomeric forms areincluded.

Compounds of the invention can exist in particular geometric orstereoisomeric forms. The invention contemplates all such compounds,including cis- and trans-isomers, (−)- and (+)-enantiomers, (R)- and(S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemicmixtures thereof, and other mixtures thereof, such as enantiomericallyor diastereomerically enriched mixtures, as falling within the scope ofthe invention. Additional asymmetric carbon atoms can be present in asubstituent such as an alkyl group. All such isomers, as well asmixtures thereof, are intended to be included in this invention.

Optically active (R)- and (S)-isomers and d and l isomers can beprepared using chiral synthons, chiral catalysts, or chiral reagents, orresolved using conventional techniques. If, for instance, a particularenantiomer of a compound of the invention is desired, it can be preparedby asymmetric synthesis, or by derivatization with a chiral auxiliary,where the resulting diastereomeric mixture is separated and theauxiliary group cleaved to provide the pure desired enantiomers.Alternatively, where the molecule contains a basic functional group,such as an amino group, or an acidic functional group, such as acarboxyl group, diastereomeric salts can be formed with an appropriateoptically active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means known in the art, and subsequent recovery of thepure enantiomers. In addition, separation of enantiomers anddiastereomers is frequently accomplished using chromatography employingchiral, stationary phases, optionally in combination with chemicalderivatization (e.g., formation of carbamates from amines).

The compounds of the invention may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example deuterium (²H), tritium (³H),iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations of thecompounds of the invention, whether radioactive or not, are intended tobe encompassed within the scope of the invention.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable vehicle” refers to any formulation or carrier medium thatprovides the appropriate delivery of an effective amount of an activeagent as defined herein, does not negatively interfere with theeffectiveness of the biological activity of the active agent, and thatis sufficiently non-toxic to the host. Representative carriers includewater, oils, both vegetable and mineral, cream bases, lotion bases,ointment bases and the like. These bases include suspending agents,thickeners, penetration enhancers, and the like. Their formulation iswell known to those in the art of topical pharmaceuticals. Additionalinformation concerning carriers can be found in Remington: The Scienceand Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins(2005) which is incorporated herein by reference.

The term “pharmaceutically acceptable excipient” is conventionally knownto mean pharmaceutically acceptable carriers, pharmaceuticallyacceptable diluents and/or pharmaceutically acceptable vehicles used informulating drug compositions effective for the desired use.

“Biological medium,” as used herein refers to both in vitro and in vivobiological milieus. Exemplary in vitro “biological media” include, butare not limited to, cell culture, tissue culture, homogenates, plasmaand blood. In vivo applications are generally performed in mammals,preferably humans.

The phrase “unit”, as used herein, refers to the number of discreteobjects to be administered which comprise the dosage form. In someembodiments, the dosage form includes a compound of the invention in onecapsule or tablet. This is a single unit. In some embodiments, thedosage form includes a compound of the invention as part of atherapeutically effective dosage of a cream or gel or ointment. This isalso a single unit. In some embodiments, the dosage form includes acompound of the invention and at least one additional therapeutic agentcontained within one capsule or tablet, or as part of a therapeuticallyeffective dosage of a cream or gel or ointment. This is a single unit,whether or not the interior of the capsule includes multiple discretegranules of the active ingredient(s). In some embodiments, the dosageform includes a compound of the invention in one capsule or tablet, andat least one additional therapeutic agent in a second capsule or tablet.This is a two unit dosage form, such as two capsules or tablets, and sosuch units are contained in a single package. Thus the term ‘unit’refers to the object which is administered to the animal, not to theinterior components of the object.

The term, “prodrug”, as defined herein, is a derivative of a parent drugmolecule that exerts its pharmacological effect only after chemicaland/or enzymatic conversion to its active form in vivo. Prodrugs includethose designed to circumvent problems associated with delivery of theparent drug. This may be due to poor physicochemical properties, such aspoor chemical stability or low aqueous solubility, and may also be dueto poor pharmacokinetic properties, such as poor bioavailability or poorhalf-life. Thus, certain advantages of prodrugs may include improvedchemical stability, absorption, and/or PK properties of the parentcarboxylic acids. Prodrugs may also be used to make drugs more “patientfriendly,” by minimizing the frequency (e.g., once daily) or route ofdosing (e.g., oral), or to improve the taste or odor if given orally, orto minimize pain if given parenterally.

In some embodiments, the prodrugs are chemically more stable than theactive drug, thereby improving formulation and delivery of the parentdrug, compared to the drug alone.

Prodrugs for carboxylic acid analogs of the invention may include avariety of esters. In an exemplary embodiment, the pharmaceuticalcompositions of the invention include a carboxylic acid ester. In anexemplary embodiment, the prodrug is suitable for treatment/preventionof those diseases and conditions that require the drug molecule to crossthe blood brain barrier. In an exemplary embodiment, the prodrug entersthe brain, where it is converted into the active form of the drugmolecule. In one embodiment, a prodrug is used to enable an active drugmolecule to reach the inside of the eye after topical application of theprodrug to the eye. Additionally, a prodrug can be converted to itsparent compound by chemical or biochemical methods in an ex vivoenvironment. For example, a prodrug can be slowly converted to itsparent compound when placed in a transdermal patch reservoir with asuitable enzyme or chemical reagent.

Boron is able to form additional covalent or dative bonds with oxygen,sulfur or nitrogen under some circumstances in this invention.

Embodiments of the invention also encompass compounds that are poly- ormulti-valent species, including, for example, species such as dimers,trimers, tetramers and higher homologs of the compounds of use in theinvention or reactive analogues thereof.

“Salt counterion”, as used herein, refers to positively charged ionsthat associate with a compound of the invention when the boron is fullynegatively or partially negatively charged. Examples of salt counterionsinclude H⁺, H₃O⁺, ammonium, potassium, calcium, magnesium, organic amino(such as choline or diethylamine or amino acids such as d-arginine,l-arginine, d-lysine, or l-lysine) and sodium.

The compounds comprising a boron bonded to a carbon and threeheteroatoms (such as three oxygens described in this section) canoptionally contain a fully negatively charged boron or partiallynegatively charged boron. Due to the negative charge, a positivelycharged counterion may associate with this compound, thus forming asalt. Examples of positively charged counterions include H⁺, H₃O⁺,ammonium, potassium, calcium, magnesium, organic amino (such as cholineor diethylamine or amino acids such as d-arginine, l-arginine, d-lysine,l-lysine), and sodium. These salts of the compounds are implicitlycontained in descriptions of these compounds.

In one aspect, the invention provides a compound of the invention. In anexemplary embodiment, the invention provides a compound describedherein. In an exemplary embodiment, the invention is a compoundaccording to a formula described herein.

The invention provides compounds having a structure of formula (I):

wherein Y is hydrogen, fluoro, chloro, or bromo;

-   -   R¹ is phenyl substituted 2-4 times, said substitutions        comprising i) 1-4 substitutions with the same or different of        halo (preferably fluoro, chloro, or bromo), and 0-1        substitutions with methyl, difluoromethyl, trifluoromethyl,        methoxy, trifluormethoxy, or trifluoroethoxy, or ii) 2        trifluoromethyl groups;    -   R² is methyl, fluoromethyl, trifluoromethyl, or perfluoroethyl;    -   R^(3a) and R^(3b) are independently selected from hydrogen,        methyl, ethyl, or fluoromethyl, or R^(3a) and R^(3b) combine        with the carbon to which they are attached to form a cyclopentyl        ring or a cyclohexyl ring;        or a salt thereof.

In an exemplary embodiment, the compound, or a salt thereof, has astructure which is a formula described herein, wherein Y, R¹, R²,R^(3a), and R^(3b) are as described herein. In an exemplary embodiment,the compound, or a salt thereof, has a structure which is formula (I),wherein Y, R¹, R², R^(3a), and R^(3b) are as described herein. In anexemplary embodiment, the compound, or a salt thereof, has a structurewhich is a formula described herein, wherein R¹, R², R^(3a), and R^(3b)are as described herein, and Y is H. In an exemplary embodiment, thecompound, or a salt thereof, has a structure which is a formuladescribed herein, wherein R¹, R², R^(3a), and R^(3b) are as describedherein, and Y is F. In an exemplary embodiment, the compound, or a saltthereof, has a structure which is a formula described herein, whereinR¹, R², R^(3a), and R^(3b) are as described herein, and Y is Cl. In anexemplary embodiment, the compound, or a salt thereof, has a structurewhich is a formula described herein, wherein R¹, R², R^(3a), and R^(3b)are as described herein, and Y is Br. In an exemplary embodiment, thecompound, or a salt thereof, has a structure which is formula (I),wherein R¹, R², R^(3a), R^(3b) and Y is H. In an exemplary embodiment,the compound, or a salt thereof, has a structure which is formula (I),wherein R¹, R², R^(3a), R^(3b) and Y is F.

In an exemplary embodiment, Y, R¹, R² and R^(3a) are as describedherein, and R^(3b) is H. In an exemplary embodiment, Y, R¹, R² andR^(3a) are as described herein, and R^(3b) is unsubstituted alkyl. In anexemplary embodiment, Y, R¹, R² and R^(3a) are as described herein, andR^(3b) is methyl or ethyl or propyl or isopropyl. In an exemplaryembodiment, Y, R¹, R² and R^(3a) are as described herein, and R^(3b) ismethyl.

In an exemplary embodiment, Y, R¹ and R² are as described herein, andR^(3a) is H and R^(3b) is H. In an exemplary embodiment, R¹ and R² areas described herein, Y is H, and R^(3a) is H and R^(3b) is H. In anexemplary embodiment, R¹ and R² are as described herein, Y is F, andR^(3a) is H and R^(3b) is H. In an exemplary embodiment, R¹ and R² areas described herein, Y is Cl, and R^(3a) is H and R^(3b) is H. In anexemplary embodiment, Y, R¹ and R² are as described herein, and R^(3a)is methyl and R^(3b) is methyl. In an exemplary embodiment, R¹ and R²are as described herein, Y is H, and R^(3a) is methyl and R^(3b) ismethyl. In an exemplary embodiment, R¹ and R² are as described herein, Yis F, and R^(3a) is methyl and R^(3b) is methyl. In an exemplaryembodiment, R¹ and R² are as described herein, Y is Cl, and R^(3a) ismethyl and R^(3b) is methyl. In an exemplary embodiment, Y, R¹ and R²are as described herein, and R^(3a) is ethyl and R^(3b) is ethyl. In anexemplary embodiment, R¹ and R² are as described herein, Y is H, andR^(3a) is ethyl and R^(3b) is ethyl. In an exemplary embodiment, R¹ andR² are as described herein, Y is F, and R^(3a) is ethyl and R^(3b) isethyl. In an exemplary embodiment, R¹ and R² are as described herein, Yis Cl, and R^(3a) is ethyl and R^(3b) is ethyl. In an exemplaryembodiment, Y, R¹ and R² are as described herein, and R^(3a) isfluoromethyl and R^(3b) is fluoromethyl. In an exemplary embodiment, R¹and R² are as described herein, Y is H, and R^(3a) is fluoromethyl andR^(3b) is fluoromethyl. In an exemplary embodiment, R¹ and R² are asdescribed herein, Y is F, and R^(3a) is fluoromethyl and R^(3b) isfluoromethyl. In an exemplary embodiment, R¹ and R² are as describedherein, Y is Cl, and R^(3a) is fluoromethyl and R^(3b) is fluoromethyl.

In an exemplary embodiment, R¹ and R² are as described herein, Y is H,and R^(3a) is H and R^(3b) is methyl. In an exemplary embodiment, R¹ andR² are as described herein, Y is F, and R^(3a) is H and R^(3b) ismethyl. In an exemplary embodiment, R¹ and R² are as described herein, Yis Cl, and R^(3a) is H and R^(3b) is methyl. In an exemplary embodiment,R¹ and R² are as described herein, Y is H, and R^(3a) is H and R^(3b) isethyl. In an exemplary embodiment, R¹ and R² are as described herein, Yis F, and R^(3a) is H and R^(3b) is ethyl. In an exemplary embodiment,R¹ and R² are as described herein, Y is Cl, and R^(3a) is H and R^(3b)is ethyl. In an exemplary embodiment, R¹ and R² are as described herein,Y is H, and R^(3a) is H and R^(3b) is fluoromethyl. In an exemplaryembodiment, R¹ and R² are as described herein, Y is F, and R^(3a) is Hand R^(3b) is fluoromethyl. In an exemplary embodiment, R¹ and R² are asdescribed herein, Y is Cl, and R^(3a) is H and R^(3b) is fluoromethyl.In an exemplary embodiment, R¹ and R² are as described herein, Y is H,and R^(3a) is methyl and R^(3b) is ethyl. In an exemplary embodiment, R¹and R² are as described herein, Y is F, and R^(3a) is methyl and R^(3b)is ethyl. In an exemplary embodiment, R¹ and R² are as described herein,Y is Cl, and R^(3a) is methyl and R^(3b) is ethyl. In an exemplaryembodiment, R¹ and R² are as described herein, Y is H, and R^(3a) ismethyl and R^(3b) is fluoromethyl. In an exemplary embodiment, R¹ and R²are as described herein, Y is F, and R^(3a) is methyl and R^(3b) isfluoromethyl. In an exemplary embodiment, R¹ and R² are as describedherein, Y is Cl, and R^(3a) is methyl and R^(3b) is fluoromethyl. In anexemplary embodiment, R¹ and R² are as described herein, Y is H, andR^(3a) is ethyl and R^(3b) is fluoromethyl. In an exemplary embodiment,R¹ and R² are as described herein, Y is F, and R^(3a) is ethyl andR^(3b) is fluoromethyl. In an exemplary embodiment, R¹ and R² are asdescribed herein, Y is Cl, and R^(3a) is ethyl and R^(3b) isfluoromethyl.

In an exemplary embodiment, Y, R¹, R^(3a) and R^(3b) are as describedherein, and R² is methyl. In an exemplary embodiment, Y, R¹, R^(3a) andR^(3b) are as described herein, and R² is fluoromethyl. In an exemplaryembodiment, Y, R¹, R^(3a) and R^(3b) are as described herein, and R² istrifluoromethyl. In an exemplary embodiment, Y, R¹, R^(3a) and R^(3b)are as described herein, and R² is perfluoromethyl. In an exemplaryembodiment, Y and R¹ are as described herein, R² is methyl, R^(3a) is Hand R^(3b) is H. In an exemplary embodiment, R¹ is as described herein,R² is methyl, Y is H, and R^(3a) is H and R^(3b) is H. In an exemplaryembodiment, R¹ is as described herein, R² is methyl, Y is F, and R^(3a)is H and R^(3b) is H. In an exemplary embodiment, R¹ is as describedherein, R² is methyl, Y is Cl, and R^(3a) is H and R^(3b) is H. In anexemplary embodiment, Y and R¹ are as described herein, R² isfluoromethyl, R^(3a) is methyl and R^(3b) is methyl. In an exemplaryembodiment, R¹ is as described herein, R² is fluoromethyl, Y is H, andR^(3a) is methyl and R^(3b) is methyl. In an exemplary embodiment, R¹ isas described herein, R² is fluoromethyl, Y is F, and R^(3a) is methyland R^(3b) is methyl. In an exemplary embodiment, R¹ is as describedherein, R² is fluoromethyl, Y is Cl, and R^(3a) is methyl and R^(3b) ismethyl. In an exemplary embodiment, Y, R¹ and R² are as describedherein, and R^(3a) is ethyl and R^(3b) is ethyl. In an exemplaryembodiment, R¹ is as described herein, R² is trifluoromethyl, Y is H,and R^(3a) is ethyl and R^(3b) is ethyl. In an exemplary embodiment, R¹is as described herein, R² is trifluoromethyl, Y is F, and R^(3a) isethyl and R^(3b) is ethyl. In an exemplary embodiment, R¹ is asdescribed herein, R² is trifluoromethyl, Y is Cl, and R^(3a) is ethyland R^(3b) is ethyl. In an exemplary embodiment, Y, R¹ and R² are asdescribed herein, and R^(3a) is fluoromethyl and R^(3b) is fluoromethyl.In an exemplary embodiment, R¹ is as described herein, R² isperfluoromethyl, Y is H, and R^(3a) is fluoromethyl and R^(3b) isfluoromethyl. In an exemplary embodiment, R¹ is as described herein, R²is perfluoromethyl, Y is F, and R^(3a) is fluoromethyl and R^(3b) isfluoromethyl. In an exemplary embodiment, R¹ is as described herein, R²is perfluoromethyl, Y is Cl, and R^(3a) is fluoromethyl and R^(3b) isfluoromethyl.

In an exemplary embodiment, R¹ and R² are as described herein, Y is H,and R^(3a) is H and R^(3b) is methyl. In an exemplary embodiment, R¹ andR² are as described herein, Y is F, and R^(3a) is H and R^(3b) ismethyl. In an exemplary embodiment, R¹ and R² are as described herein, Yis Cl, and R^(3a) is H and R^(3b) is methyl. In an exemplary embodiment,R¹ and R² are as described herein, Y is H, and R^(3a) is H and R^(3b) isethyl. In an exemplary embodiment, R¹ and R² are as described herein, Yis F, and R^(3a) is H and R^(3b) is ethyl. In an exemplary embodiment,R¹ and R² are as described herein, Y is Cl, and R^(3a) is H and R^(3b)is ethyl. In an exemplary embodiment, R¹ and R² are as described herein,Y is H, and R^(3a) is H and R^(3b) is fluoromethyl. In an exemplaryembodiment, R¹ and R² are as described herein, Y is F, and R^(3a) is Hand R^(3b) is fluoromethyl. In an exemplary embodiment, R¹ and R² are asdescribed herein, Y is Cl, and R^(3a) is H and R^(3b) is fluoromethyl.In an exemplary embodiment, R¹ and R² are as described herein, Y is H,and R^(3a) is methyl and R^(3b) is ethyl. In an exemplary embodiment, R¹and R² are as described herein, Y is F, and R^(3a) is methyl and R^(3b)is ethyl. In an exemplary embodiment, R¹ and R² are as described herein,Y is Cl, and R^(3a) is methyl and R^(3b) is ethyl. In an exemplaryembodiment, R¹ and R² are as described herein, Y is H, and R^(3a) ismethyl and R^(3b) is fluoromethyl. In an exemplary embodiment, R¹ and R²are as described herein, Y is F, and R^(3a) is methyl and R^(3b) isfluoromethyl. In an exemplary embodiment, R¹ and R² are as describedherein, Y is Cl, and R^(3a) is methyl and R^(3b) is fluoromethyl. In anexemplary embodiment, R¹ and R² are as described herein, Y is H, andR^(3a) is ethyl and R^(3b) is fluoromethyl. In an exemplary embodiment,R¹ and R² are as described herein, Y is F, and R^(3a) is ethyl andR^(3b) is fluoromethyl. In an exemplary embodiment, R¹ and R² are asdescribed herein, Y is Cl, and R^(3a) is ethyl and R^(3b) isfluoromethyl.

In an exemplary embodiment, Y and R¹ are as described herein, R² istrifluoromethyl, R^(3a) is H and R^(3b) is H. In an exemplaryembodiment, R¹ is as described herein, R² is trifluoromethyl, Y is H,and R^(3a) is H and R^(3b) is H. In an exemplary embodiment, R¹ is asdescribed herein, R² is trifluoromethyl, Y is F, and R^(3a) is H andR^(3b) is H. In an exemplary embodiment, R¹ is as described herein, R²is trifluoromethyl, Y is Cl, and R^(3a) is H and R^(3b) is H. In anexemplary embodiment, Y and R¹ are as described herein, R² istrifluoromethyl, and R^(3a) is methyl and R^(3b) is methyl. In anexemplary embodiment, R¹ is as described herein, R² is trifluoromethyl,Y is H, and R^(3a) is methyl and R^(3b) is methyl. In an exemplaryembodiment, R¹ is as described herein, R² is trifluoromethyl, Y is F,and R^(3a) is methyl and R^(3b) is methyl. In an exemplary embodiment,R¹ is as described herein, R² is trifluoromethyl, Y is Cl, and R^(3a) ismethyl and R^(3b) is methyl. In an exemplary embodiment, Y and R¹ are asdescribed herein, R² is trifluoromethyl, and R^(3a) is ethyl and R^(3b)is ethyl. In an exemplary embodiment, R¹ is as described herein, R² istrifluoromethyl, Y is H, and R^(3a) is ethyl and R^(3b) is ethyl. In anexemplary embodiment, R¹ is as described herein, R² is trifluoromethyl,Y is F, and R^(3a) is ethyl and R^(3b) is ethyl. In an exemplaryembodiment, R¹ is as described herein, R² is trifluoromethyl, Y is Cl,and R^(3a) is ethyl and R^(3b) is ethyl. In an exemplary embodiment, Yand R¹ are as described herein, R² is trifluoromethyl, R^(3a) isfluoromethyl and R^(3b) is fluoromethyl. In an exemplary embodiment, R¹is as described herein, R² is trifluoromethyl, Y is H, and R^(3a) isfluoromethyl and R^(3b) is fluoromethyl. In an exemplary embodiment, R¹is as described herein, R² is trifluoromethyl, Y is F, and R^(3a) isfluoromethyl and R^(3b) is fluoromethyl. In an exemplary embodiment, R¹is as described herein, R² is trifluoromethyl, Y is Cl, and R^(3a) isfluoromethyl and R^(3b) is fluoromethyl.

In an exemplary embodiment, R¹ is as described herein, R² istrifluoromethyl, Y is H, and R^(3a) is H and R^(3b) is methyl. In anexemplary embodiment, R¹ is as described herein, R² is trifluoromethyl,Y is F, and R^(3a) is H and R^(3b) is methyl. In an exemplaryembodiment, R¹ is as described herein, R² is trifluoromethyl, Y is Cl,and R^(3a) is H and R^(3b) is methyl. In an exemplary embodiment, R¹ isas described herein, R² is trifluoromethyl, Y is H, and R^(3a) is H andR^(3b) is ethyl. In an exemplary embodiment, R¹ is as described herein,R² is trifluoromethyl, Y is F, and R^(3a) is H and R^(3b) is ethyl. Inan exemplary embodiment, R¹ is as described herein, R² istrifluoromethyl, Y is Cl, and R^(3a) is H and R^(3b) is ethyl. In anexemplary embodiment, R¹ is as described herein, R² is trifluoromethyl,Y is H, and R^(3a) is H and R^(3b) is fluoromethyl. In an exemplaryembodiment, R¹ is as described herein, R² is trifluoromethyl, Y is F,and R^(3a) is H and R^(3b) is fluoromethyl. In an exemplary embodiment,R¹ is as described herein, R² is trifluoromethyl, Y is Cl, and R^(3a) isH and R^(3b) is fluoromethyl. In an exemplary embodiment, R¹ is asdescribed herein, R² is trifluoromethyl, Y is H, and R^(3a) is methyland R^(3b) is ethyl. In an exemplary embodiment, R¹ is as describedherein, R² is trifluoromethyl, Y is F, and R^(3a) is methyl and R^(3b)is ethyl. In an exemplary embodiment, R¹ is as described herein, R² istrifluoromethyl, Y is Cl, and R^(3a) is methyl and R^(3b) is ethyl. Inan exemplary embodiment, R¹ is as described herein, R² istrifluoromethyl, Y is H, and R^(3a) is methyl and R^(3b) isfluoromethyl. In an exemplary embodiment, R¹ is as described herein, R²is trifluoromethyl, Y is F, and R^(3a) is methyl and R^(3b) isfluoromethyl. In an exemplary embodiment, R¹ is as described herein, R²is trifluoromethyl, Y is Cl, and R^(3a) is methyl and R^(3b) isfluoromethyl. In an exemplary embodiment, R¹ is as described herein, R²is trifluoromethyl, Y is H, and R^(3a) is ethyl and R^(3b) isfluoromethyl. In an exemplary embodiment, R¹ is as described herein, R²is trifluoromethyl, Y is F, and R^(3a) is ethyl and R^(3b) isfluoromethyl. In an exemplary embodiment, R¹ is as described herein, R²is trifluoromethyl, Y is Cl, and R^(3a) is ethyl and R^(3b) isfluoromethyl.

In an exemplary embodiment, the compound has a structure according tothe following formula:

wherein Y, R¹, R², R^(3a) and R^(3b) are as described herein, and C* isa carbon atom which is a stereocenter having a configuration which is(R) or (S). In an exemplary embodiment, Y, R¹, R², R^(3a) and R^(3b) areas described herein, and C* is a stereocenter with a (R) configuration.In an exemplary embodiment, Y, R¹, R², R^(3a) and R^(3b) are asdescribed herein, and C* is a stereocenter with a (S) configuration.

The invention further provides compounds of the structure

wherein C* is a carbon atom which is a stereocenter having a (S)configuration, or a salt thereof. The invention further providescompound of the structure:

-   wherein R^(1b), R^(1c), and R^(1d) are each independently selected    from hydrogen, fluoro, chloro, bromo, methyl, difluoromethyl,    trifluoromethyl, methoxy, trifluormethoxy, or trifluoroethoxy, and    -   R^(3a) and R^(3b) are selected from CH₃ or CH₂F, and salts        thereof.

The invention further provides compounds of the structure:

wherein R² is CF₃; and R^(1b), R^(1c), and R^(1d) are each independentlyselected from hydrogen, fluoro, chloro, or bromo or a salt thereof, andcompounds wherein R² is CF₃, R^(1b) is fluoro, chloro, or bromo; R^(1c)is hydrogen, fluoro, or chloro; and R^(id) is fluoro, chloro, or bromo,or a salt thereof.

The following table provides examples of the compound of the invention,according to the formula

R^(1b) R^(1c) R^(1d) F F H H H F H H H F F F H F H F H F F F F F Cl Cl HH H Cl H H H Cl Cl Cl H Cl H Cl H Cl Cl Cl Cl Cl Br Br H H H Br H H H BrBr Br H Br H Br H Br Br Br Br Br F, Cl F Cl H Cl F H F H Cl Cl H F H FCl H Cl F Cl F F F Cl F F F Cl Cl Cl F Cl F Cl F Cl Cl F, Br F Br H Br FH F H Br Br H F H F Br H Br F Br F F F Br F F F Br Br Br F Br F Br F BrBr Br, Cl Br Cl H Cl Br H Br H Cl Cl H Br H Br Cl H Cl Br Cl Br Br Br ClBr Br Br Cl Cl Cl Br Cl Br Cl Br Cl Cl

In an exemplary embodiment, according to any entries in this table, Y isas described herein, R² is CF₃ or CHF₂ or CH₂F, R^(3a) is CH₃ and R^(3b)is CH₃. In an exemplary embodiment, according to any entries in thistable, Y is as described herein, R² is CF₃, R^(3a) is unsubstitutedalkyl and R^(3b) is unsubstituted alkyl. In an exemplary embodiment,according to any entries in this table, Y is as described herein, R² isCF₃, R^(3a) is ethyl and R^(3b) is ethyl. In an exemplary embodiment,according to any entries in this table, Y is as described herein, R² isCF₃, R^(3a) is CH₃ and R^(3b) is CH₃. In an exemplary embodiment,according to any entries in this table, R², R^(3a), and R^(3b) are asdescribed herein, and Y is H. In an exemplary embodiment, according toany entries in this table, R², R^(3a), and R^(3b) are as describedherein, and Y is F. In an exemplary embodiment, according to any entriesin this table, R², R^(3a), and R^(3b) are as described herein, and Y isCl. In an exemplary embodiment, according to any entries in this table,R² is as described herein, R^(3a) is CH₃ or CH₂F and R^(3b) is CH₃ orCH₂F, and Y is H. In an exemplary embodiment, according to any entriesin this table, R² is as described herein, R^(3a) is CH₃ or CH₂F andR^(3b) is CH₃ or CH₂F, and Y is F. In an exemplary embodiment, accordingto any entries in this table, R² is as described herein, R^(3a) is CH₃or CH₂F and R^(3b) is CH₃ or CH₂F, and Y is Cl. In an exemplaryembodiment, according to any entries in this table, R² is CF₃, R^(3a) isCH₃ or CH₂F and R^(3b) is CH₃ or CH₂F, and Y is H. In an exemplaryembodiment, according to any entries in this table, R² is CF₃, R^(3a) isCH₃ or CH₂F and R^(3b) is CH₃ or CH₂F, and Y is F. In an exemplaryembodiment, according to any entries in this table, R² is CF₃, R^(3a) isCH₃ or CH₂F and R^(3b) is CH₃ or CH₂F, and Y is Cl.

In an exemplary embodiment, the invention provides a compound describedherein, or a salt, hydrate or solvate thereof, or a combination thereof.In an exemplary embodiment, the invention provides a compound describedherein, or a salt, hydrate or solvate thereof. In an exemplaryembodiment, the invention provides a compound described herein, or asalt thereof. In an exemplary embodiment, the salt is a pharmaceuticallyacceptable salt. In an exemplary embodiment, the invention provides acompound described herein, or a hydrate thereof. In an exemplaryembodiment, the invention provides a compound described herein, or asolvate thereof. In an exemplary embodiment, the invention provides acompound described herein, or a prodrug thereof. In an exemplaryembodiment, the invention provides a salt of a compound describedherein. In an exemplary embodiment, the invention provides apharmaceutically acceptable salt of a compound described herein. In anexemplary embodiment, the invention provides a hydrate of a compounddescribed herein. In an exemplary embodiment, the invention provides asolvate of a compound described herein. In an exemplary embodiment, theinvention provides a prodrug of a compound described herein.

As used herein, the term “chiral”, “enantiomerically enriched” or“diastereomerically enriched” refers to a composition having anenantiomeric excess (ee) or a diastereomeric excess (de) of greater thanabout 50%, preferably greater than about 70% and more preferably greaterthan about 90%. In general, higher than about 90% enantiomeric ordiastereomeric excess is particularly preferred, e.g., thosecompositions with greater than about 95%, greater than about 97% andgreater than about 99% ee or de.

When a first compound and a second compound are present in acomposition, and the first compound is a non-superimposable mirror imageof the second compound, and the first compound is present in thecomposition in a greater amount than the second compound, then the firstcompound is referred to herein as being present in “enantiomericexcess”.

The term “enantiomeric excess” of a compound z, as used herein, isdefined as:

${ee}_{z} = {\left( \frac{{{{conc}.\mspace{14mu} {of}}\mspace{14mu} z} - {{{conc}.\mspace{14mu} {of}}\mspace{14mu} y}}{{{{conc}.\mspace{14mu} {of}}\mspace{14mu} z} + {{{conc}.\mspace{14mu} {of}}{\mspace{11mu} \;}y}} \right) \times 100}$

wherein z is a first compound in a composition, y is a second compoundin the composition, and the first compound is a non-superimposablemirror image of the second compound.

The term “enantiomeric excess” is related to the older term “opticalpurity” in that both are measures of the same phenomenon. The value ofee will be a number from 0 to 100, zero being racemic and 100 beingenantiomerically pure. A composition which in the past might have beencalled 98% optically pure is now more precisely characterized by 96% ee.A 90% ee reflects the presence of 95% of one enantiomer and 5% of theother(s) in the material in question.

When a first compound and at least one additional compound are presentin a composition, and the first compound and each of the additionalcompounds are stereoisomers, but not mirror images, of one another, andthe first compound is present in the composition in a greater amountthan each of the additional compounds, then the first compound isreferred to herein as being present in “diastereomeric excess”.

When dealing with mixtures of diastereomers, the term “diastereomericexcess” or “de” is defined analagously to enantiomeric excess. Thus:

${de}_{w} = {\left( \frac{{{{conc}.\mspace{14mu} {of}}\mspace{14mu} {major}\mspace{14mu} {diastereomer}} - {{{conc}.\mspace{14mu} {of}}\mspace{14mu} {\min {or}}\mspace{14mu} {{diastereomer}(s)}}}{{{{conc}.\mspace{14mu} {of}}\mspace{14mu} {major}\mspace{14mu} {diastereomer}} + {{{conc}.\mspace{14mu} {of}}\mspace{14mu} \min \; {or}{\mspace{11mu} \;}{{diastereomer}(s)}}} \right) \times 100}$

wherein the major diastereomer is a first compound in a composition, andthe minor diastereomer(s) is at least one additional compound in thecomposition, and the major diastereomer and minor diastereomer(s) arestereoisomers, but not mirror images, of one another.

The value of de will likewise be a number from 0 to 100, zero being anequal mixture of a first diastereomer and the remaining diastereomer(s),and 100 being 100% of a single diastereomer and zero % of theother(s)—i.e. diastereomerically pure. Thus, 90% de reflects thepresence of 95% of one diastereomer and 5% of the other diastereomer(s)in the material in question.

Hence, in one embodiment, the invention provides a composition includinga first compound of the invention, wherein the first compound of theinvention has at least one stereocenter, and at least one stereoisomerof the first compound of the invention. In another embodiment, theinvention provides a composition including a first compound of theinvention, wherein the first compound of the invention has at least onestereocenter, and a second compound of the invention, wherein the firstcompound of the invention is a stereoisomer of the second compound ofthe invention. In another embodiment, the invention provides acomposition including a first compound of the invention, wherein thefirst compound of the invention has at least one stereocenter, and onlyone stereoisomer of the first compound of the invention.

In another embodiment, the invention provides a composition including afirst compound of the invention, wherein the first compound of theinvention has only one stereocenter, and an enantiomer of the firstcompound of the invention. In another embodiment, the invention providesa composition including a first compound of the invention, wherein thefirst compound of the invention has two stereocenters, and an enantiomerof the first compound of the invention. In another embodiment, theinvention provides a composition including a first compound of theinvention, wherein the first compound of the invention has twostereocenters, and at least one diasteromer of the first compound of theinvention. In another embodiment, the invention provides a compositionincluding a first compound of the invention, wherein the first compoundof the invention has two stereocenters, and only one diasteromer of thefirst compound of the invention.

In situations where the first compound of the invention and itsenantiomer are present in a composition, the first compound of theinvention can be present in an enantiomeric excess of at least about80%, or at least about 90%, or at least about 92% or at least about 95%.In another embodiment, where the first compound of the invention and itsenantiomer are present in a composition, the first compound of theinvention can be present in an enantiomeric excess of at least about96%, at least about 97%, at least about 98%, at least about 99% or atleast about 99.5%. In another embodiment, the first compound of theinvention has at least one stereocenter and is enantiomerically pure(enantiomeric excess is about 100%).

In situations where the first compound of the invention and at least onediastereomer of the first compound of the invention are present in acomposition, the first compound of the invention can be present in adiastereomeric excess of at least about 80%, or at least about 90%, orat least about 92% or at least about 95%. In situations where the firstcompound of the invention and at least one diastereomer of the firstcompound of the invention are present in a composition, the firstcompound of the invention can be present in a diastereomeric excess ofat least about 96%, at least about 97%, at least about 98%, at leastabout 99% or at least about 99.5%. In another embodiment, the firstcompound of the invention has at least two stereocenters and isdiastereomerically pure (diastereomeric excess is about 100%).

Enantiomeric or diastereomeric excess can be determined relative toexactly one other stereoisomer, or can be determined relative to the sumof at least two other stereoisomers. In an exemplary embodiment,enantiomeric or diastereomeric excess is determined relative to allother detectable stereoisomers, which are present in the mixture.Stereoisomers are detectable if a concentration of such stereoisomer inthe analyzed mixture can be determined using common analytical methods,such as chiral HPLC.

As used herein, and unless otherwise indicated, a composition that is“substantially free” of a compound means that the composition containsless than about 20% by weight, or less than about 15% by weight, or lessthan about 10% by weight, or less than about 5% by weight, or less thanabout 3% by weight, or less than about 2% by weight, or less than about1% by weight of the compound.

As used herein, the term “substantially free of the (or its) enantiomer”means that a composition contains a significantly greater proportion ofa first compound of the invention than a second compound of theinvention, wherein the first compound is a non-superimposable mirrorimage of the second compound. In one embodiment of the invention, theterm “substantially free of the enantiomer” means that the compositionis made up of at least about 90% by weight of a first compound of theinvention, and about 10% by weight or less of a second compound of theinvention, wherein the first compound is a non-superimposable mirrorimage of the second compound. In one embodiment of the invention, theterm “substantially free of the (R) enantiomer” means that thecomposition is made up of at least about 90% by weight of a firstcompound of the invention which has only one stereocenter and thestereocenter is in an (S) configuration, and about 10% by weight or lessof a second compound of the invention, wherein the second compound isthe enantiomer of the first compound. In one embodiment of theinvention, the term “substantially free of the enantiomer” means thatthe composition is made up of at least about 95% by weight of a firstcompound of the invention, and about 5% by weight or less of a secondcompound of the invention, wherein the first compound is anon-superimposable mirror image of the second compound. In oneembodiment of the invention, the term “substantially free of the (R)enantiomer” means that the composition is made up of at least about 95%by weight of a first compound of the invention which has only onestereocenter and the stereocenter is in an (S) configuration, and about5% by weight or less of a second compound of the invention, wherein thesecond compound is the enantiomer of the first compound. In oneembodiment of the invention, the term “substantially free of theenantiomer” means that the composition is made up of at least about 98%by weight of a first compound of the invention, and about 2% by weightor less of a second compound of the invention, wherein the firstcompound is a non-superimposable mirror image of the second compound. Inone embodiment of the invention, the term “substantially free of the (R)enantiomer” means that the composition is made up of at least about 98%by weight of a first compound of the invention which has only onestereocenter and the stereocenter is in an (S) configuration, and about2% by weight or less of a second compound of the invention, wherein thesecond compound is the enantiomer of the first compound. In oneembodiment of the invention, the term “substantially free of theenantiomer” means that the composition is made up of at least about 99%by weight of a first compound of the invention, and about 1% by weightor less of a second compound of the invention, wherein the firstcompound is a non-superimposable mirror image of the second compound. Inone embodiment of the invention, the term “substantially free of the (R)enantiomer” means that the composition is made up of at least about 99%by weight of a first compound of the invention which has only onestereocenter and the stereocenter is in an (S) configuration, and about1% by weight or less of a second compound of the invention, wherein thesecond compound is the enantiomer of the first compound.

In an exemplary embodiment, the invention provides a compositioncomprising a) first compound described herein; and b) the enantiomer ofthe first compound, wherein the first compound described herein ispresent in an enantiomeric excess of at least 80%. In an exemplaryembodiment, the enantiomeric excess is at least 92%. In anotherexemplary embodiment, the first compound described herein has anisoxazolinyl moiety, and one carbon atom in the isoxazolinyl moiety is astereocenter, and the stereocenter is in a (S) configuration, and thestereocenter is the only stereocenter in the first compound. In anotherexemplary embodiment, the first compound described herein has anisoxazolinyl moiety, and one carbon atom in the isoxazolinyl moiety is astereocenter, and the stereocenter is in a (R) configuration, and thestereocenter is the only stereocenter in the first compound.

In an exemplary embodiment, the invention provides a compositioncomprising a first compound described herein with an isoxazolinylmoiety, and one carbon atom in the isoxazolinyl moiety is astereocenter, and the stereocenter is in a (S) configuration, and saidcomposition is substantially free of the enantiomer of the firstcompound described herein. In an exemplary embodiment, the inventionprovides a composition comprising a first compound described herein withan isoxazolinyl moiety, and one carbon atom in the isoxazolinyl moietyis a stereocenter, and the stereocenter is in a (R) configuration, andsaid composition is substantially free of the enantiomer of the firstcompound described herein.

The compounds of the invention may also be used in combination withadditional therapeutic agents. The invention thus provides, in a furtheraspect, a combination comprising a compound described herein or apharmaceutically acceptable salt thereof together with at least oneadditional therapeutic agent. The invention thus provides, in a furtheraspect, a combination comprising a compound described herein or apharmaceutically acceptable salt thereof together with one additionaltherapeutic agent. The invention thus provides, in a further aspect, acombination comprising a compound described herein or a pharmaceuticallyacceptable salt thereof together with two additional therapeutic agents.The invention thus provides, in a further aspect, a combinationcomprising a compound described herein or a pharmaceutically acceptablesalt thereof together with a first additional therapeutic agent and asecond additional therapeutic agent. In an exemplary embodiment, theadditional therapeutic agent is a compound of the invention. In anexemplary embodiment, the additional therapeutic agent includes a boronatom. In an exemplary embodiment, the additional therapeutic agent doesnot contain a boron atom.

When a compound of the invention is used in combination with a secondtherapeutic agent active against the same disease state, the dose ofeach compound may differ from that when the compound is used alone.Appropriate doses will be readily appreciated by those skilled in theart. It will be appreciated that the amount of a compound of theinvention required for use in treatment will vary with the nature of thecondition being treated and the age and the condition of the patient andwill be ultimately at the discretion of the attendant physician orveterinarian. In an exemplary embodiment, the additional therapeuticagent is an acaricide. In an exemplary embodiment, the additionaltherapeutic agent is an ixodicide. In an exemplary embodiment, theadditional therapeutic agent is a miticide. In an exemplary embodiment,the additional therapeutic agent is pyrethrine. In an exemplaryembodiment, the additional therapeutic agent is permethin or pyrethrumor phenothrin. In an exemplary embodiment, the additional therapeuticagent is a chloride channel inhibitor. In an exemplary embodiment, theadditional therapeutic agent is an avermectin. In an exemplaryembodiment, the additional therapeutic agent is selamectin or doramectinor abamectin. In an exemplary embodiment, the additional therapeuticagent is ivermectin. In an exemplary embodiment, the additionaltherapeutic agent is a milbemycin. In an exemplary embodiment, theadditional therapeutic agent is milbemectin or moxidectin or nemadectin.In an exemplary embodiment, the additional therapeutic agent ismilbemycin oxime. In an exemplary embodiment, a first additionaltherapeutic agent is milbemycin oxime and a second additionaltherapeutic agent is a spinosad. In an exemplary embodiment, theadditional therapeutic agent is an organophosphate. In an exemplaryembodiment, the additional therapeutic agent is malathion. In anexemplary embodiment, the additional therapeutic agent is lindane. In anexemplary embodiment, the additional therapeutic agent is disulfiram. Inan exemplary embodiment, the additional therapeutic agent is benzylbenzoate. In an exemplary embodiment, the additional therapeutic agentis fipronil. In an exemplary embodiment, the additional therapeuticagent comprises an isoxazoline moiety. In an exemplary embodiment, theadditional therapeutic agent is Nissan A1443.

In an exemplary embodiment, the additional therapeutic agent is aspinosad. In an exemplary embodiment, the additional therapeutic agentis a spinosad or a salt, (e.g. pharmaceutically acceptable salt),prodrug, solvate or hydrate thereof. Spinosad is a member of thespinosyns class of insecticides, which are non-antibacterial tetracyclicmacrolides. Spinosad contains two major factors, spinosyn A and spinosynD. Spinosyn A and spinosyn D are known as2-[(6-deoxy-2,3,4-tri-O-methyl-α-L-mannopyranosyl)oxy]-13-[[5-dimethylamino)-tetrahydro-6-methyl-2H-pyran-2-yl]oxy]-9-ethyl-2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b-tetradecahydro-14-methyl-1H-as-Indaceno[3,2-d]oxacyclododecin-7,15-dioneand2-[(6-deoxy-2,3,4-tri-O-methyl-α-L-mannopyranosyl)oxy]-13-[[5-dimethylamino)-tetrahydro-6-methyl-2H-pyran-2-yl]oxy]-9-ethyl-2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16btetradecahydro-4,14-dimethyl-1H-as-Indaceno[3,2-d]oxacyclododecin-7,15-dione,respectively. Spinosyn A and spinosyn D have a structure according tothe following formula:

In an exemplary embodiment, the additional therapeutic agent isspinetoram. In an exemplary embodiment, the additional therapeutic agentis spinosyn A. In an exemplary embodiment, the additional therapeuticagent is spinosyn A or a salt, (e.g. pharmaceutically acceptable salt),prodrug, solvate or hydrate thereof. In an exemplary embodiment, theadditional therapeutic agent is spinosyn D. In an exemplary embodiment,the additional therapeutic agent is spinosyn D or a salt, (e.g.pharmaceutically acceptable salt), prodrug, solvate or hydrate thereof.In exemplary embodiments, Comfortis® is administered in combination witha compound described herein, optionally with a pharmaceuticallyacceptable excipient. In exemplary embodiments, any pharmaceuticalformulation comprising a spinosad (e.g., a pharmaceutical formulationcomprising (a) a pharmaceutically acceptable excipient; (b) a compoundof the invention and (c) a spinosad (e.g., spinosyn A or spinosyn D) isadministered orally. In exemplary embodiments, any pharmaceuticalformulation comprising a spinosad is administered to kill or inhibit thegrowth of fleas. In exemplary embodiments, any pharmaceuticalformulation comprising a spinosad is administered to kill or inhibit thegrowth of ticks.

The individual components of such combinations may be administeredeither simultaneously or sequentially in a unit dosage form. The unitdosage form may be a single or multiple unit dosage forms. In anexemplary embodiment, the invention provides a combination in a singleunit dosage form. An example of a single unit dosage form is a capsulewherein both the compound of the invention and the additionaltherapeutic agent are contained within the same capsule. In an exemplaryembodiment, the invention provides a combination in a two unit dosageform. An example of a two unit dosage form is a first capsule whichcontains the compound of the invention and a second capsule whichcontains the additional therapeutic agent. Thus the term ‘single unit’or ‘two unit’ or ‘multiple unit’ refers to the object which the patientingests, not to the interior components of the object. Appropriate dosesof known therapeutic agents will be readily appreciated by those skilledin the art.

The combinations referred to herein may be presented for use as apharmaceutical formulation. Thus, an exemplary embodiment of theinvention is a pharmaceutical formulation comprising a) a compound ofthe invention; b) an additional therapeutic agent and c) apharmaceutically acceptable excipient. Thus, an exemplary embodiment ofthe invention is a pharmaceutical formulation comprising a) a compoundof the invention; b) a first additional therapeutic agent; c) a secondadditional therapeutic agent and d) a pharmaceutically acceptableexcipient. In an exemplary embodiment, the pharmaceutical formulation isa unit dosage form. In an exemplary embodiment, the pharmaceuticalformulation is a single unit dosage form. In an exemplary embodiment,the pharmaceutical formulation is a two unit dosage form. In anexemplary embodiment, the pharmaceutical formulation is a two unitdosage form comprising a first unit dosage form and a second unit dosageform, wherein the first unit dosage form includes a) a compound of theinvention and b) a first pharmaceutically acceptable excipient; and thesecond unit dosage form includes c) an additional therapeutic agent andd) a second pharmaceutically acceptable excipient.

In one aspect, the invention is a combination comprising: a) a compoundof the invention; and b) at least one additional therapeutic agent. Inan exemplary embodiment, the invention is a combination comprising: a) acompound of the invention; and b) an additional therapeutic agent. Inanother exemplary embodiment, the combination comprises: a) a compoundof the invention; b) a first additional therapeutic agent; and c) asecond additional therapeutic agent. In another exemplary embodiment,the combination comprises: a) a compound of the invention; b) a firstadditional therapeutic agent; c) a second additional therapeutic agent;and d) a third additional therapeutic agent. The first additionaltherapeutic agent or second additional therapeutic agent or thirdadditional therapeutic agent can be selected from the additionaltherapeutic agents described in this document.

It is to be understood that the invention covers all combinations ofaspects and/or embodiments, as well as suitable, convenient andpreferred groups described herein.

Compounds of use in the invention can be prepared using commerciallyavailable starting materials, known intermediates, or by using thesynthetic methods described herein, or published in references describedand incorporated by reference herein, such as PCT Pub. No. WO2008157726and U.S. Pat. Pubs. US20060234981, US20070155699 and US20070293457.

In one embodiment, the compound of the invention can be synthesizedaccording to the following scheme:

(where R^(1e) can be hydrogen, R^(1b), R^(1c), or R^(1d)), whereinboronic acid-related A is commercially available from, for example,Sigma-Aldrich. A can also be synthesized from the corresponding arylbromide using well known conventional methods available in theliterature. A can be converted to B through Suzuki coupling reaction. Ccan be converted to D through subjecting it to esterification reactionconditions, such as those involving thionyl chloride and alcohol. D canbe converted to E through subjecting it to reducing conditions, such asthose involving LiAlH₄. E can be converted to F through subjecting it tooxidation conditions, such as those involving MnO₂. F can be convertedto G through subjecting it to oxime-forming reaction conditions, such asthose involving hydroxylamine G can be converted to H through subjectingit to chlorination reaction conditions, such as those involving NCS. Hcan be converted to I through subjecting it to cyclization reaction withB. I can be converted to J through subjecting it to bromination reactionconditions, such as those involving NBS. J can be converted to K throughsubjecting it to substitution conditions, such as that involving sodiumacetate. K can be converted to L through subjecting it to boronylationreaction conditions, such as those involving bis(pinacolato)diboron. Lcan be converted to M through subjecting it to hydrolysis conditions,such as those involving aqueous lithium hydroxide and then aqueoushydrochloric acid.

In one embodiment, the compound of the invention can be synthesizedaccording to the following scheme:

wherein N is commercially available from, for example, Sigma-Aldrich. Ncan be converted to O through subjecting it to esterification reactionconditions, such as those involving thionyl chloride and alcohol. O canbe converted to P through subjecting it to Grignard reaction conditions,such as that involving alkyl magnesium bromide (R^(3a) and R^(3b) aresame in this scheme). P can be converted to Q through subjecting it toboronylation conditions. Q can be converted to R through subjecting itto dibromination and hydrolysis conditions, such as those involving 2 eqNBS and then aqueous sodium carbonate. R can be converted to S throughsubjecting it to oxime-forming conditions, such as those involvinghydroxylamine. S can be converted to T through subjecting it tochlorination conditions, such as that involving NCS. T can be convertedto U through subjecting it to cyclization reaction with B.

In one embodiment, the compound of the invention can be synthesizedaccording to the following scheme:

wherein V is commercially available from, for example, Sigma-Aldrich. Vcan be converted to W through subjecting it to iodination reactionconditions, such as those involving I₂. W can be converted to X throughsubjecting it to Sandmeyer reaction conditions, such as those involvingHNO₂ and then CuBr. X can be converted to P through subjecting it toGrignard-reagent-forming condition and then addition reaction to ketones(R^(3a) and R^(3b) can be same or different in this scheme). The rest ofthe reaction conditions in this scheme are same as described in theprevious scheme.

Compounds described herein can be converted into hydrates and solvatesby methods similar to those described herein.

The compounds of the invention exhibit potency against ectoparasites andtherefore have the potential to kill and/or inhibit the growth ofectoparasites. The compounds of the invention exhibit potency againstinsects and thus have the potential to kill and/or inhibit the growth ofinsects.

In a further aspect, the invention provides a method of killing and/orinhibiting the growth of an ectoparasite, said method comprising:contacting said ectoparasite with an effective amount of a compound ofthe invention, thereby killing and/or inhibiting the growth of theectoparasite. In an exemplary embodiment, the ectoparasite is an acari.In an exemplary embodiment, the ectoparasite is a tick. In an exemplaryembodiment, the ectoparasite is a mite. In an exemplary embodiment, thecompound is described herein, or a salt, prodrug, hydrate or solvatethereof, or a combination thereof. In an exemplary embodiment, theinvention provides a compound described herein, or a salt, hydrate orsolvate thereof. In an exemplary embodiment, the invention provides acompound described herein, or a prodrug thereof. In an exemplaryembodiment, the invention provides a compound described herein, or asalt thereof. In another exemplary embodiment, the compound of theinvention is a compound described herein, or a pharmaceuticallyacceptable salt thereof. In another exemplary embodiment, the compoundis described by a formula listed herein, or a pharmaceuticallyacceptable salt thereof. In an exemplary embodiment, the compound ispart of a pharmaceutical formulation described herein. In anotherexemplary embodiment, the contacting occurs under conditions whichpermit entry of the compound into the organism.

In another aspect, the ectoparasite is on the surface of an animal. Inanother aspect, the ectoparasite is in an animal. In an exemplaryembodiment, the animal is selected from the group consisting of human,cattle, deer, reindeer, goat, honey bee, pig, sheep, horse, cow, bull,dog, guinea pig, gerbil, rabbit, cat, camel, yak, elephant, ostrich,otter, chicken, duck, goose, guinea fowl, pigeon, swan, and turkey. Inanother exemplary embodiment, the animal is a human. In an exemplaryembodiment, the animal is a warm-blooded animal.

In another aspect, the ectoparasite is on the surface of a plant. Inanother aspect, the ectoparasite is in a plant.

In an exemplary embodiment, the ectoparasite is killed or its growth isinhibited through oral administration of the compound of the invention.In an exemplary embodiment, the ectoparasite is killed or its growth isinhibited through intravenous administration of the compound of theinvention. In an exemplary embodiment, the ectoparasite is killed or itsgrowth is inhibited through subcutaneous administration of the compoundof the invention.

In an exemplary embodiment, the ectoparasite is an insect. In anexemplary embodiment, the insect is selected from the group consistingof Lepidoptera, Coleoptera, Homoptera, Hemiptera, Heteroptera, Diptera,Dictyoptera, Thysanoptera, Orthoptera, Anoplura, Siphonaptera,Mallophaga, Thysanura, lsoptera, Psocoptera and Hymenoptera. However,the ectoparasites which may be mentioned in particular are those whichtrouble humans or animals and carry pathogens, for example flies such asMusca domestica, Musca vetustissima, Musca autumnalis, Fanniecanicularis, Sarcophage carnaria, Lucilia cuprina, Lucilia sericata,Hypoderma bovis, Hypoderma lineatum, Chrysomyia chloropyga, Dermatobiehominis, Cochliomyia hominivorax, Gasterophilus intestinaiis, Oestrusovis, biting flies such as Haematobia irritans irritans, Haematobiairritans exigua, Stomoxys calcitrans, horse-flies (Tabanids) with thesublarnilies of Tabanidae such as Haematopota spp. (e.g. Haematopotapluvialis) and Tabanus spp, e.g. Tabanus nigrovittatus) and Chrysopsineesuch as Chrysops spp. (e.g. Chrysops caecutlens); Hippoboscids such asMelophagus ovinus (sheep ked); tsetse flies, such as Glossinia sop;other biting insects like midges, such as Ceratopogonidae (bitingmidges), Simuliidse (Blackflies), Psychodidae (Sandflies); but alsoblood-sucking insects, for example mosquitoes, such as Anopheles spp,Aedes sop and Culex spp, fleas, such as Ctenocephalides felis andCtenocephalides canis (cat and dog fleas, respectively), Xenopsyllacheopis, Pulex irritans, Ceratophyilus galfinae, Dermatophiluspenetrans, blood-sucking lice (Anoplura) such as Linognathus spp,Haematopinus spp, Olenopotes spp, Pediculus humanis; but also chewinglice (Mallophaga) such as Bovicola (Damalinia) ovis, Bovicola(Darnalinia) bovis and other Bovicola spp. Ectoparasites also includemembers of the order Acarina, such as mites (e.g. Chorioptes bovis,Cheyletiella spp., Dermanyasus galiinae, Ortnithonyssus spp., Demodexcants, Sarcoptes scabiei, Psoroptes ovis and Psorergates spp. In anexemplary embodiment, the insect is a tick or flea.

In an exemplary embodiment, the ectoparasite is a fly. In an exemplaryembodiment, the ectoparasite is a member of the Oestridae family. In anexemplary embodiment, the ectoparasite is a bot. In an exemplaryembodiment, the ectoparasite is a horse bot. In an exemplary embodiment,the insect is a member of the Gasterophilus genus. In an exemplaryembodiment, the insect is Gasterophilus nasalis or Gasterophilusintestinalis or Gasterophilus haemorrhoidalis or Gasterophilus inermisor Gasterophilus nigricomis or Gasterophilus pecorum. In an exemplaryembodiment, the insect is Gasterophilus nasalis or Gasterophilusintestinalis or Gasterophilus haemorrhoidalis.

In an exemplary embodiment, the tick is a hard tick. In an exemplaryembodiment, the tick is a soft tick. In an exemplary embodiment, thetick is a Nuttalliellidae tick. In an exemplary embodiment, the tick isan Argasidae tick. In an exemplary embodiment, the tick is an Antricolatick or Argas tick or Nothaspis tick or Ornithodoros tick or Otobiustick. In an exemplary embodiment, the tick is an Ixodidae tick. In anexemplary embodiment, the tick is an Amblyomma tick. In an exemplaryembodiment, the tick is a Dermacentor tick. In an exemplary embodiment,the tick is a Rhipicephalus tick. In an exemplary embodiment, the tickis a Rhipicephalus tick. In an exemplary embodiment, the tick is anAnomalohimalaya tick or Bothriocroton tick or Cosmiomma tick orCornupalpatum tick or Compluriscutula tick or Haemaphysalis tick orHyalomma tick or Ixodes tick or Margaropus tick or Nosomma tick orRhipicentor tick. In an exemplary embodiment, the tick is anOrnithodorus tick. In an exemplary embodiment, the ectoparasite is aBoophilus tick or an Anocentor tick. In an exemplary embodiment, theectoparasite is a tick which is selected from the group consisting ofIxodes scapularis, Ixodes holocyclus, Ixodes pacificus, Rhiphicephalussanguineus, Dermacentor andersoni, Dermacentor variabilis, Amblyommaamericanum, Ambryomma maculatum, Ornithodorus hermsi, Ornithodorusturicata.

In an exemplary embodiment, the ectoparasite is a mite which is selectedfrom the group consisting of Parasitiformes and Mesostigmata. In anexemplary embodiment, the ectoparasite is a mite which is Ornithonyssusbacoti or Dermanyssus gallinae.

In an exemplary embodiment, the ectoparasite is a mite. In an exemplaryembodiment, the mite is Arcarina or Tetranychidae. In an exemplaryembodiment, the mite is Tetranychus spp. or Panonychus spp. In anexemplary embodiment, the mite is a trombiculid mite. In an exemplaryembodiment, the mite is chigger.

In an exemplary embodiment, the ectoparasite is a flea. In an exemplaryembodiment, the flea (Siphonaptera) is a Ctenocephalides flea orXenopsylla flea or Pulex flea or Tunga flea or Dasypsyllus flea orNosopsyllus flea. In an exemplary embodiment, the flea (Siphonaptera) isCtenocephalides felis or Ctenocephalides canis or Xenopsylla cheopis orPulex irritan or Tunga penetrans or Dasypsyllus gallinulae orNosopsyllus fasciatus.

The compounds described herein according to the invention are alsoactive against all or individual development stages of animal pestsshowing normal sensitivity, as well as those showing resistance towidely used parasiticides. This is especially true for resistant insectsand members of the order Acarina. The insecticidal, ovicidal and/oracaricidal effect of the active substances of the invention can manifestitself directly, i.e. killing the pests either immediately or after sometime has elapsed, for example when moulting occurs, or by destroyingtheir eggs, or indirectly, e.g. reducing the number of eggs laid and/orthe hatching rate.

The compounds described herein can also be used against hygiene pests,especially of the order Diptera of the families Muscidae, Saroophagidae,Anophilidae and Cuticidae; the orders Orthoptera, Dictyoptera (e.g. thefamily Blattidae (cockroaches), such as Blatella germanica, Blattaonentalis, Periplaneta americana) and Hymenoptera (e.g. the familiesFormicidae (ants) and Vespidae (wasps)).

They have high activity against sucking insects of the order Hornoptera,especially against pests of the families Aphididee, Delphacidae,Cicadellidea Psyllidae, Diaspididae and Eriophydidae (e.g. rust mite oncitrus fruits); the orders Hemiptera, Hetsroptera and Thysenoptera, andon the plant-eating insects of the orders Lepidoptera, Coleoptera,Diptera and Orthoptera. In an exemplary embodiment, the insect isCimicidae. In an exemplary embodiment, the insect is Cimex lectularius.In an exemplary embodiment, the insect is a bed bug.

In an exemplary embodiment, the ectoparasite is lice. In an exemplaryembodiment, the lice (Phthiraptera), e.g. Pediculus humanus capitis,Pediculus humanus corporis, Pthirus pubis, Haematopinus eurysternus,Haematopinus suis, Linognathus vituli, Bovicola bovis, Menopon gallinae,Menacanthus stramineus and Solenopotes capillatus.

In an exemplary embodiment, the ectoparasite is an ectoparasite offishes. In an exemplary embodiment, the ectoparasite is Copepoda (e.g.order of Siphonostomatoidae) (sea lice).

Diseases transmitted through ectoparasites, particularly blood-feedingectoparasites such as ticks, biting and muscoid flies, reduvid bugs,mosquitos, mites, and fleas, include, for example, bacterial, viral andprotozoal diseases. Non-vector born pathological conditions associatedwith ectoparasite infestations include, for example, flea-allergydermatitis (FAD) associated with flea infestations; secondarydematological infections associated with heavy ectoparasite burden(i.e., face-fly infestations in cattle herds and ear-mite induced otitisexterna in dogs), and tick paralysis associated with various tickspecies. Mites are implicated in scabies and rosacea. The compounds ofthe invention are effective in the treatment and control ofectoparasites implicated or suspected in development of diseases inanimals, such as mammals and birds, and therefore have the potential toindirectly ameliorate, reduce or prevent such diseases associated withectoparasite infestations in the animals described herein. The compoundsof the invention are effective in the treatment and control ofectoparasites implicated or suspected in development of diseases inplants, and therefore have the potential to indirectly ameliorate,reduce or prevent such diseases associated with ectoparasiteinfestations in the plants described herein.

In one embodiment, arbovirus (arthropod-borne virus) diseases associatedwith an ectoparasite include, for example, Crimean-Congo HemmorhagicFever (CCHF), Febrile illness, Papataci fever, Encephalitis andMeningitis, which are caused by Bunyaviridae such as Bunyavirus,Nairovirus and Phlebovirus; Bluetongue, meningoencephalits, Febrileillness, hemorhagic fever, which are caused by Reoviridae such asOrbivirus and Colitivirus; Febrile illness, rash, encephalitis,polyarthritis, lymphadenitis which are caused by Togaviridae, such asSindbisvirus and Chikungunya Virus; tick-borne meningoencephalitis,Dengue hemmorhagic fever, encephalitis, Febrile illness or West NileFever, and Yellow fever which are caused by Flaviviridae, such asFlavivirus (including diverse sub-groups); West Nile virus. In anotherembodiment, bacterial diseases transmitted by ectoparasites include, forexample, Rocky Mountain spotted fever, tick typhus caused by infectionthrough Rickettsia spp; Q-fever caused by Coxiella burnetii; Tularemiacaused by infection through Francisella tularensis; Borreliosis orSpirochaetosis, such as Lyme disease, or relapsing fever, caused byinfection through Borrelia spp.; Ehrlichiosis caused by infectionthrough Ehrlichia spp.; Plague, caused by infection through Yersiniapestis. In another embodiment, protozoan or rickettsial diseasestransmitted by ectoparasites include, for example, Babesiosis, such asTexas fever, red water disease, caused by infection through Babesiaspp.; Theileriosis, such as east coast fever, Mediterranean coast fever,caused by infection through Theileria spp.; Nagana disease, Sleepingsickness caused by infection through Trypanosoma spp., Anaplasmosiscaused by infection through Anaplasma spp.; Malaria caused by infectionthrough Plasmodium spp.; Leishmaniasis caused by infection throughLeishmania spp.

In an exemplary embodiment, the invention provides a method of reducingthe size of an ectoparasitic infestation in or on an animal in need oftreatment thereof. The method includes administering to the animal atherapeutically effective amount of the compound of the invention,sufficient to reduce the size of the ectoparasitic infestation. In anexemplary embodiment, the invention provides a method of reducing thesize of an ectoparasitic infestation in or on a plant in need oftreatment thereof. The method includes administering to the plant atherapeutically effective amount of the compound of the invention,sufficient to reduce the size of the ectoparasitic infestation.

In an exemplary embodiment, the invention provides a method ofcontrolling an ectoparasitic infestation in or on an animal in need oftreatment thereof. The method includes administering to the animal atherapeutically effective amount of the compound of the invention,sufficient to control the ectoparasitic infestation. In an exemplaryembodiment, controlling an ectoparasitic infestation is reducing thenumber of ectoparasites in or on an animal. In an exemplary embodiment,the invention provides a method of controlling an ectoparasiticinfestation in or on a plant in need of treatment thereof. The methodincludes administering to the plant a therapeutically effective amountof the compound of the invention, sufficient to control theectoparasitic infestation. In an exemplary embodiment, controlling anectoparasitic infestation is reducing the number of ectoparasites in oron a plant.

In an exemplary embodiment, the invention provides a method ofpreventing an ectoparasitic infestation in or on an animal in need oftreatment thereof. The method includes administering to the animal aprophylactically effective amount of the compound of the invention,sufficient to prevent the ectoparasitic infestation. In an exemplaryembodiment, the invention provides a method of preventing anectoparasitic infestation in or on a plant in need of treatment thereof.The method includes administering to the plant a prophylacticallyeffective amount of the compound of the invention, sufficient to preventthe ectoparasitic infestation.

In an exemplary embodiment, the invention provides a method of reducingthe transmission, in an animal, of a disease transmitted through anectoparasite. The method includes administering to the animal in needthereof a therapeutically effective amount of the compound of theinvention, sufficient to reduce the spread of the disease-causing agentfrom the ectoparasite to the animal. In an exemplary embodiment, theinvention provides a method of reducing the transmission, in a plant, ofa disease transmitted through an ectoparasite. The method includesadministering to the plant in need thereof a therapeutically effectiveamount of the compound of the invention, sufficient to reduce the spreadof the disease-causing agent from the ectoparasite to the plant.

In an exemplary embodiment, the compound is described herein, or a salt,prodrug, hydrate or solvate thereof, or a combination thereof. In anexemplary embodiment, the invention provides a compound describedherein, or a salt, hydrate or solvate thereof. In an exemplaryembodiment, the invention provides a compound described herein, or aprodrug thereof. In an exemplary embodiment, the invention provides acompound described herein, or a salt thereof. In another exemplaryembodiment, the compound of the invention is a compound describedherein, or a pharmaceutically acceptable salt thereof. In anotherexemplary embodiment, the compound is described by a formula listedherein, or a pharmaceutically acceptable salt thereof. In an exemplaryembodiment, the compound is part of a pharmaceutical formulationdescribed herein. Such conditions are known to one skilled in the artand specific conditions are set forth in the Examples appended hereto.

In an exemplary embodiment, the compound is described herein, or a salt,prodrug, hydrate or solvate thereof, or a combination thereof. In anexemplary embodiment, the invention provides a compound describedherein, or a salt, hydrate or solvate thereof. In an exemplaryembodiment, the invention provides a compound described herein, or aprodrug thereof. In an exemplary embodiment, the invention provides acompound described herein, or a salt thereof. In another exemplaryembodiment, the compound of the invention is a compound describedherein, or a pharmaceutically acceptable salt thereof. In anotherexemplary embodiment, the compound is described by a formula listedherein, or a pharmaceutically acceptable salt thereof. In an exemplaryembodiment, the compound is part of a pharmaceutical formulationdescribed herein. Such conditions are known to one skilled in the artand specific conditions are set forth in the Examples appended hereto.

In another exemplary embodiment, the animal is a member selected fromhuman, cattle, deer, reindeer, goat, honey bee, pig, sheep, horse, cow,bull, dog, guinea pig, gerbil, rabbit, cat, camel, yak, elephant,ostrich, otter, chicken, duck, goose, guinea fowl, pigeon, swan, andturkey. In another exemplary embodiment, the animal is a human. Inanother exemplary embodiment, the animal is a non-human mammal. Inanother exemplary embodiment, the animal is a mammal. In anotherexemplary embodiment, the animal is a domestic animal. In anotherexemplary embodiment, the animal is a domestic mammal. In anotherexemplary embodiment, the animal is a companion animal. In anotherexemplary embodiment, the animal is a companion mammal. In anotherexemplary embodiment, the animal is a dog. In another exemplaryembodiment, the animal is a cat. In another exemplary embodiment, theanimal is a rodent. In another exemplary embodiment, the animal is arat. In another exemplary embodiment, the animal is a mouse. In anotherexemplary embodiment, the animal is a member selected from goat, pig,sheep, horse, cow, bull, dog, guinea pig, gerbil, rabbit, cat, chickenand turkey. In another exemplary embodiment, the animal is an ungulate.In another exemplary embodiment, the ungulate is selected from the groupconsisting of horse, zebra, donkey, cattle/bison, rhinoceros, camel,hippopotamus, goat, pig, sheep, giraffe, okapi, moose, elk, deer, tapir,antelope, and gazelle. In another exemplary embodiment, the ungulate iscattle. In another exemplary embodiment, the ungulate is selected fromthe group consisting of goat, pig, and sheep. In another exemplaryembodiment, the animal is a ruminant. In another exemplary embodiment,the ruminant is selected from the group consisting of cattle, goats,sheep, giraffes, bison, yaks, water buffalo, deer, camels, alpacas,llamas, wildebeast, antelope, pronghorn, and nilgai. In anotherexemplary embodiment, the cattle is a cow. In another exemplaryembodiment, the cattle is a bull. In another exemplary embodiment, thecattle is a calf. In another exemplary embodiment, the animal is anequine. In another exemplary embodiment, the animal is selected from thegroup consisting of horse, donkey, caribou and reindeer. In anotherexemplary embodiment, the animal is a horse. In another exemplaryembodiment, the animal is a snail. In another exemplary embodiment, theanimal is an insect. In another exemplary embodiment, the animal is amosquito. In another exemplary embodiment, the animal is a fly.

In an exemplary embodiment, the disease is treated through oraladministration of the compound of the invention. In an exemplaryembodiment, the disease is treated through intravenous administration ofthe compound of the invention. In an exemplary embodiment, the diseaseis treated through topical administration of the compound of theinvention. In an exemplary embodiment, the disease is treated throughintraperitoneal administration of the compound of the invention. In anexemplary embodiment, the disease is treated through subcutaneousinjection of the compound of the invention. In an exemplary embodiment,the compound is administered in a topically effective amount. In anexemplary embodiment, the pharmaceutical formulation is administered inan orally effective amount. In an exemplary embodiment, the compound isadministered in an effective amount via subcutaneous injection.

Given their activity, the compounds of the invention are suitable assoil insecticides against pests in the soil, as well as insecticides forplants, such as cereals, cotton, rice, maize, soya, potatoes,vegetables, fruit, tobacco, hops, citrus, and avocados. The compoundsaccording to the invention are suitable for protecting plants and plantorgans, for increasing the harvest yields, and for improving the qualityof the harvested material which are encountered in agriculture, inhorticulture, in forests, in gardens, and leisure facilities, and in theprotection of stored products and of materials. They may be employed asplant protection agents. Therefore, the compounds of the invention canbe used to treat a disease in a plant, or kill or inhibit the growth ofa worm that affects a plant.

All plants and plant parts can be treated in accordance with theinvention. Plants are to be understood as meaning in the present contextall plants and plant populations such as desired and undesired wildplants or crop plants (including naturally occurring crop plants). Cropplants can be plants which can be obtained by conventional plantbreeding and optimization methods or by biotechnological and geneticengineering methods or by combinations of these methods, including thetransgenic plants and including the plant cultivars protectable or notprotectable by plant breeders' rights. Plant parts are to be understoodas meaning all parts and organs of plants above and below the ground,such as shoot, leaf, flower and root, examples which may be mentionedbeing leaves, needles, stalks, stems, flowers, fruit bodies, fruits,seeds, roots, tubers and rhizomes. The plant parts also includeharvested material, and vegetative and generative propagation material,for example cuttings, tubers, rhizomes, offshoots and seeds.

Treatment according to the invention of the plants and plant parts withthe active compounds is carried out by conventional and known means,including directly acting on, or by allowing the compounds to act on,the surroundings, habitat or storage space by the customary treatmentmethods, for example by immersion, spraying, evaporation, fogging,scattering, painting on, injection and, in the case of propagationmaterial, in particular in the case of seeds, also by applying one ormore coats.

The active compounds can be converted to the customary formulations,such as solutions, emulsions, wettable powders, water- and oil-basedsuspensions, powders, dusts, pastes, soluble powders, soluble granules,granules for broadcasting, suspension-emulsion concentrates, naturalmaterials impregnated with active compound, synthetic materialsimpregnated with active compound, fertilizers and microencapsulations inpolymeric substances.

In another aspect, the invention is a pharmaceutical formulation whichincludes: (a) a pharmaceutically acceptable excipient; and (b) acompound of the invention. In another aspect, the pharmaceuticalformulation includes: (a) a pharmaceutically acceptable excipient; and(b) a compound according to a formula described herein. In anotheraspect, the pharmaceutical formulation includes: (a) a pharmaceuticallyacceptable excipient; and (b) a compound described herein, or a salt,prodrug, hydrate or solvate thereof, or a combination thereof. Inanother aspect, the pharmaceutical formulation includes: (a) apharmaceutically acceptable excipient; and (b) a compound describedherein, or a salt, hydrate or solvate thereof, or a combination thereof.In another aspect, the pharmaceutical formulation includes: (a) apharmaceutically acceptable excipient; and (b) a compound describedherein, or a salt, hydrate or solvate thereof. In another aspect, thepharmaceutical formulation includes: (a) a pharmaceutically acceptableexcipient; and (b) a salt of a compound described herein. In anexemplary embodiment, the salt is a pharmaceutically acceptable salt. Inan exemplary embodiment, the pharmaceutically acceptable excipient is apharmaceutically acceptable carrier. In an exemplary embodiment, thepharmaceutically acceptable excipient is a pharmaceutically acceptablediluent. In an exemplary embodiment, the pharmaceutically acceptableexcipient is a pharmaceutically acceptable vehicle. In another aspect,the pharmaceutical formulation includes: (a) a pharmaceuticallyacceptable excipient; and (b) a prodrug of a compound described herein.In another aspect, the pharmaceutical formulation includes: (a) apharmaceutically acceptable excipient; and (b) a compound describedherein. In an exemplary embodiment, the pharmaceutical formulation is aunit dosage form. In an exemplary embodiment, the pharmaceuticalformulation is a single unit dosage form. In an exemplary embodiment, apharmaceutical formulation described herein can be administered to ananimal described herein. In an exemplary embodiment, a pharmaceuticalformulation described herein can be administered to a human. In anexemplary embodiment, a pharmaceutical formulation described herein isadministered to a non-human mammal described herein. In an exemplaryembodiment, a pharmaceutical formulations described herein can beadministered to a plant described herein.

The pharmaceutical formulations of the invention can take a variety offorms adapted to the chosen route of administration. Those skilled inthe art will recognize various synthetic methodologies that may beemployed to prepare non-toxic pharmaceutical formulations incorporatingthe compounds described herein. Those skilled in the art will recognizea wide variety of non-toxic pharmaceutically acceptable solvents thatmay be used to prepare solvates of the compounds of the invention, suchas water, ethanol, propylene glycol, mineral oil, vegetable oil anddimethylsulfoxide (DMSO).

The pharmaceutical formulation of the invention may be administeredorally, topically, intraperitoneally, parenterally, by inhalation orspray or rectally in unit dosage forms containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles. It isfurther understood that the best method of administration may be acombination of methods. Oral administration in the form of a pill,chewable tablet, capsule, elixir, syrup, spray, lozenge, troche, or thelike is particularly preferred. The term parenteral as used hereinincludes subcutaneous injections, intradermal, intravascular (e.g.,intravenous), intramuscular, spinal, intrathecal injection or likeinjection or infusion techniques. Topical administration as used hereinincludes application of liquid and/or solid and/or semi-solidformulations as dermal spot-ons, sprays, dips, pour-ons, dusts orpowders, ointments, and feed-throughs. In an exemplary embodiment, thepharmaceutical formulation is administered orally. In an exemplaryembodiment, the pharmaceutical formulation is administeredintravenously. In an exemplary embodiment, the pharmaceuticalformulation is administered in a topically effective dose. In anexemplary embodiment, the pharmaceutical formulation is administered inan orally effective dose.

The pharmaceutical formulations containing compounds of the inventioncan be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known in the art for the manufacture of pharmaceuticalformulations, and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets may containthe active ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia; and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withpharmaceutically acceptable excipients suitable for the manufacture ofaqueous suspensions. Such excipients are suspending agents, for examplesodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gumtragacanth and gum acacia; and dispersing or wetting agents, which maybe a naturally-occurring phosphatide, for example, lecithin, orcondensation products of an alkylene oxide with fatty acids, for examplepolyoxyethylene stearate, or condensation products of ethylene oxidewith long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives, for exampleethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents, and one or more sweetening agents, such assucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional pharmaceutically acceptable excipients, for examplesweetening, flavoring and coloring agents, may also be present.

Pharmaceutical formulations of the invention may also be in the form ofoil-in-water emulsions and water-in-oil emulsions. The oily phase may bea vegetable oil, for example olive oil or arachis oil, or a mineral oil,for example liquid paraffin or mixtures of these. Suitable emulsifyingagents may be naturally-occurring gums, for example gum acacia or gumtragacanth; naturally-occurring phosphatides, for example soy bean,lecithin, and esters or partial esters derived from fatty acids andhexitol; anhydrides, for example sorbitan monooleate; and condensationproducts of the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, and flavoring and coloringagents. The pharmaceutical formulations may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents, which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The composition of the invention may also be administered in the form ofsuppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating pharmaceutically acceptable excipient that is solid atordinary temperatures but liquid at the rectal temperature and willtherefore melt in the rectum to release the drug. Such materials arecocoa butter and polyethylene glycols.

Alternatively, the compositions can be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.

For administration to non-human animals, the composition containing thetherapeutic compound may be added to the animal's feed or drinkingwater. Also, it will be convenient to formulate animal feed and drinkingwater products so that the animal takes in an appropriate quantity ofthe compound in its diet. It will further be convenient to present thecompound in a composition as a premix for addition to the feed ordrinking water. The composition can also added as a food or drinksupplement for humans.

Dosage levels of the order of from about 0.01 mg to about 3500 mg perkilogram of body weight per day, about 0.01 mg to about 1000 mg perkilogram of body weight per day, or from about 0.1 mg to about 100 mgper kilogram of body weight per day, or from about 5 mg to about 250 mgper kilogram of body weight per day, or from about 25 mg to about 150 mgper kilogram of body weight per day, are useful in the treatment of theabove-indicated conditions. The amount of active ingredient that may becombined with the carrier materials to produce a unit dosage form willvary depending upon the condition being treated and the particular modeof administration. Unit dosage forms will generally contain between fromabout 1 mg to about 3500 mg of an active ingredient. In an exemplaryembodiment, an effective amount can be selected from a dosage rangeprovided in this document. In an exemplary embodiment, a therapeuticallyeffective amount can be selected from a dosage range provided in thisdocument. In an exemplary embodiment, a prophylatically effective amountcan be selected from a dosage range provided in this document. In anexemplary embodiment, an orally effective amount can be selected from adosage range provided in this document. In an exemplary embodiment, atopically effective amount can be selected from a dosage range providedin this document.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. In an exemplary embodiment, the compositionof the invention is administered once a day or twice a day or threetimes a day or four times a day. In an exemplary embodiment, thecomposition of the invention is administered once a week or twice a weekor three times a week or four times a week. In an exemplary embodiment,the composition of the invention is administered once a month or twice amonth or three times a month or four times a month. It will beunderstood, however, that the specific dose level for any particularanimal or plant will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

In an exemplary embodiment, the unit dosage form contains from about 1mg to about 800 mg of a compound of the invention. In an exemplaryembodiment, the unit dosage form contains from about 1 mg to about 500mg of an active ingredient. In an exemplary embodiment, the unit dosageform contains from about 100 mg to about 800 mg of a compound of theinvention. In an exemplary embodiment, the unit dosage form containsfrom about 200 mg to about 500 mg of a compound of the invention. In anexemplary embodiment, the unit dosage form contains from about 500 mg toabout 800 mg of a compound of the invention. In an exemplary embodiment,the unit dosage form contains from about 1 mg to about 100 mg of acompound of the invention. In an exemplary embodiment, the unit dosageform contains from about 10 mg to about 100 mg of a compound of theinvention. In an exemplary embodiment, the unit dosage form containsfrom about 50 mg to about 100 mg of a compound of the invention. In anexemplary embodiment, the unit dosage form contains from about 75 mg toabout 200 mg of a compound of the invention. In an exemplary embodiment,the unit dosage form contains from about 1 mg to about 5 mg of acompound of the invention. In an exemplary embodiment, the unit dosageform contains from about 10 mg to about 25 mg of a compound of theinvention. In an exemplary embodiment, the unit dosage form containsfrom about 50 mg to about 350 mg of a compound of the invention. In anexemplary embodiment, the unit dosage form contains from about 200 mg toabout 400 mg of a compound of the invention. In an exemplary embodiment,the unit dosage form contains from about 800 mg to about 3500 mg of acompound of the invention. In an exemplary embodiment, the unit dosageform contains from about 800 mg to about 3000 mg of a compound of theinvention. In an exemplary embodiment, the unit dosage form containsfrom about 2000 mg to about 3000 mg of a compound of the invention. Inan exemplary embodiment, the unit dosage form contains from about 950 mgto about 1450 mg of a compound of the invention. In an exemplaryembodiment, the unit dosage form contains from about 1450 mg to about1950 mg of a compound of the invention. In an exemplary embodiment, theunit dosage form contains from about 1950 mg to about 2450 mg of acompound of the invention. In an exemplary embodiment, the unit dosageform contains from about 2450 mg to about 2950 mg of a compound of theinvention.

In an exemplary embodiment, the daily dosage contains from about 1 mg toabout 800 mg of a compound of the invention. In an exemplary embodiment,the daily dosage contains from about 1 mg to about 500 mg of an activeingredient. In an exemplary embodiment, the daily dosage contains fromabout 100 mg to about 800 mg of a compound of the invention. In anexemplary embodiment, the daily dosage contains from about 200 mg toabout 500 mg of a compound of the invention. In an exemplary embodiment,the daily dosage contains from about 500 mg to about 800 mg of acompound of the invention. In an exemplary embodiment, the daily dosagecontains from about 1 mg to about 100 mg of a compound of the invention.In an exemplary embodiment, the daily dosage contains from about 10 mgto about 100 mg of a compound of the invention. In an exemplaryembodiment, the daily dosage contains from about 50 mg to about 100 mgof a compound of the invention. In an exemplary embodiment, the dailydosage contains from about 75 mg to about 200 mg of a compound of theinvention. In an exemplary embodiment, the daily dosage contains fromabout 1 mg to about 5 mg of a compound of the invention. In an exemplaryembodiment, the daily dosage contains from about 10 mg to about 25 mg ofa compound of the invention. In an exemplary embodiment, the dailydosage contains from about 50 mg to about 350 mg of a compound of theinvention. In an exemplary embodiment, the daily dosage contains fromabout 200 mg to about 400 mg of a compound of the invention. In anexemplary embodiment, the daily dosage contains from about 800 mg toabout 3500 mg of a compound of the invention. In an exemplaryembodiment, the daily dosage contains from about 800 mg to about 3000 mgof a compound of the invention. In an exemplary embodiment, the dailydosage contains from about 2000 mg to about 3000 mg of a compound of theinvention. In an exemplary embodiment, the daily dosage contains fromabout 950 mg to about 1450 mg of a compound of the invention. In anexemplary embodiment, the daily dosage contains from about 1450 mg toabout 1950 mg of a compound of the invention. In an exemplaryembodiment, the daily dosage contains from about 1950 mg to about 2450mg of a compound of the invention. In an exemplary embodiment, the dailydosage contains from about 2450 mg to about 2950 mg of a compound of theinvention.

Preferred compounds of the invention will have desirable pharmacologicalproperties that include, but are not limited to, oral bioavailability,low toxicity, low serum protein binding and desirable in vitro and invivo half-lives. Penetration of the blood brain barrier for compoundsused to treat CNS disorders is necessary, while low brain levels ofcompounds used to treat peripheral disorders are often preferred.

Assays may be used to predict these desirable pharmacologicalproperties. Assays used to predict bioavailability include transportacross human intestinal cell monolayers, including Caco-2 cellmonolayers. Toxicity to cultured hepatocyctes may be used to predictcompound toxicity. Penetration of the blood brain barrier of a compoundin humans may be predicted from the brain levels of laboratory animalsthat receive the compound intravenously.

Serum protein binding may be predicted from albumin binding assays. Suchassays are described in a review by Oravcova, et al. (Journal ofChromatography B (1996) volume 677, pages 1-27).

In vitro half-lives of compounds may be predicted from assays ofmicrosomal half-life as described by Kuhnz and Gieschen (Drug Metabolismand Disposition, (1998) volume 26, pages 1120-1127).

The amount of the composition required for use in treatment will varynot only with the particular compound selected but also with the routeof administration, the nature of the condition being treated and the ageand condition of the animal or plant and will ultimately be at thediscretion of the attendant physician or veterinarian or agronomist.

Preferred compounds for use in the pharmaceutical formulations describedherein will have certain pharmacological properties. Such propertiesinclude, but are not limited to, low toxicity, low serum protein bindingand desirable in vitro and in vivo half-lives. Assays may be used topredict these desirable pharmacological properties. Assays used topredict bioavailability include transport across human intestinal cellmonolayers, including Caco-2 cell monolayers. Serum protein binding maybe predicted from albumin binding assays. Such assays are described in areview by Oravcova et al. (1996, J. Chromat. B677: 1-27). Compoundhalf-life is inversely proportional to the frequency of dosage of acompound. In vitro half-lives of compounds may be predicted from assaysof microsomal half-life as described by Kuhnz and Gleschen (DrugMetabolism and Disposition, (1998) volume 26, pages 1120-1127).

Toxicity and therapeutic efficacy of such compounds can be determined bystandard pharmaceutical procedures in cell cultures or experimentalanimals, e.g., for determining the LD50 (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dose ratio between toxic and therapeutic effects isthe therapeutic index and it can be expressed as the ratio between LD₅₀and ED₅₀. Compounds that exhibit high therapeutic indices are preferred.The data obtained from these cell culture assays and animal studies canbe used in formulating a range of dosage for use in animals (such ashumans) or plants. The dosage of such compounds can lie within a rangeof circulating concentrations that include the ED₅₀ with little or notoxicity. The dosage can vary within this range depending upon the unitdosage form employed and the route of administration utilized. The exactformulation, route of administration and dosage can be chosen by theindividual physician in view of the patient's condition. (See, e.g.Fingl et al., 1975, in “The Pharmacological Basis of Therapeutics”, Ch.1, p. 1).

For a compound or composition utilized for a method described herein,the therapeutically effective dose can be estimated initially fromvarious in vitro assays, as disclosed herein. For example, a dose can beformulated in animal models to achieve a circulating concentration rangethat includes the EC₅₀ (effective dose for 50% increase) as determinedin vitro, i.e., the concentration of the test compound which achieves ahalf-maximal lethality toward a parasite, pest or other organism ofinterest. Such information can be used to more accurately determineuseful doses.

In general, the compounds prepared by the methods, and from theintermediates, described herein will be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. It will beunderstood, however, that the specific dose level for any particularanimal or plant will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination, the severity ofthe particular disease undergoing therapy and the judgment of theprescribing entity. The drug can be administered once a day or twice aday or three times a day or four times a day, or once a week or twice aweek or three times a week or four times a week or once a month or twicea month or three times a month or four times a month.

Dosage amount and interval can be adjusted individually to provideplasma levels of the active moiety that are sufficient to maintain cellgrowth inhibitory effects.

The amount of the compound in a formulation can vary within the fullrange employed by those skilled in the art. Typically, the formulationwill contain, on a weight percent (wt %) basis, from about 0.01-60 wt %of the drug based on the total formulation, with the balance being oneor more suitable pharmaceutically acceptable excipients.

Exemplary embodiments, according to any of the above paragraphs, include5-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol;or(S)-5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol; or(R)-5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(3,5-Dibromophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(3-Chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or3,3-Dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(3,5-Dichloro-4-methylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(3,5-Dichloro-4-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol; or5-(5-(3,5-Dichloro-4-(difluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol; or5-(5-(3,5-Dichloro-4-(trifluoromethoxy)phenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(3,5-Dichlorophenyl)-5-(perfluoroethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(3,5-Bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(3,5-Dichloro-4-(2,2,2-trifluoroethoxyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or3,3-Dimethyl-5-(5-methyl-5-(3,4,5-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol;or(S)-3,3-Dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol;or(R)-3,3-Dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(3-Chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(Fluoromethyl)-5-(3,4,5-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(4-Bromo-3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(3,5-Dichloro-4-methoxyphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(3,4-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(4-Fluoro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(3-Chloro-4,5-difluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(3,4-Dichloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(3,5-Dibromo-4-chlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or(S)-5-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or(R)-5-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(4-Chloro-3,5-difluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or3,3-Dimethyl-5-(5-(trifluoromethyl)-5-(3,4,5-trifluorophenyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(3,5-Dibromo-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or3,3-Bis(fluoromethyl)-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol;or3,3-Dimethyl-5-(5-(2,3,4,5-tetrachlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(3,5-Dichloro-2,4-difluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-diethyl-benzo[c][1,2]oxaborol-1(3H)-ol;or5-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1H-spiro[benzo[c][1,2]oxaborole-3,1′-cyclopentan]-1-ol;or5-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1H-spiro[benzo[c][1,2]oxaborole-3,1′-cyclohexan]-1-ol;or5-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4-fluoro-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or4-Fluoro-3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol; or5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-6-fluoro-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or6-Fluoro-3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol.

In an exemplary embodiment, the invention provides a combinationcomprising a compound according to any of the above paragraphs, togetherwith at least one additional therapeutic agent.

In an exemplary embodiment, the invention provides a pharmaceuticalformulation comprising: (a) a compound according to any of the aboveparagraphs; and (b) a pharmaceutically acceptable excipient.

In an exemplary embodiment, according to any of the above paragraphs,the pharmaceutical formulation is a unit dosage form.

In an exemplary embodiment, the salt of a compound according to any ofthe above paragraphs is a pharmaceutically acceptable salt.

In an exemplary embodiment, the invention is a method of killing and/orpreventing the growth of an ectoparasite, comprising: contacting theectoparasite with an effective amount of a compound according to any ofthe above paragraphs, thereby killing and/or preventing the growth ofthe ectoparasite.

In an exemplary embodiment, according to any of the above paragraphs,the ectoparasite is a tick or a flea.

In an exemplary embodiment, according to any of the above paragraphs,the ectoparasite is in or on an animal.

In an exemplary embodiment, the invention is a method of controlling anectoparasitic infestation in or on an animal in need of treatmentthereof, comprising: administering to the animal a therapeuticallyeffective amount of a compound according to any of the above paragraphs,sufficient to control the ectoparasitic infestation.

In an exemplary embodiment, according to any of the above paragraphs,the animal is a dog or a cat.

In an exemplary embodiment, the invention is a use of the compoundaccording to any of the above paragraphs in the manufacture of amedicament for the treatment and/or prophylaxis of ectoparasiticinfection.

The invention is further illustrated by the Examples that follow. TheExamples are not intended to define or limit the scope of the invention.

All solvents used were commercially available and were used withoutfurther purification. Reactions were typically run using anhydroussolvents under an inert atmosphere of N₂.

¹H, ¹³C, and ¹⁹F NMR spectra were recorded at 400 MHz for proton, 100MHz for carbon-13, and 376 MHz for fluorine-19 on a Varian 300MercuryPlus station with an Oxford AS400 Spectrometer equipped with aVarian 400 ATB PFG probe. All deuterated solvents typically contained0.03% to 0.05% v/v tetramethylsilane, which was used as the referencesignal (set at δ 0.00 for both ¹H and ¹³C).

Compounds are named using ChemDraw 7.0 or their catalogue name ifcommercially available.

Mass spectra were recorded on a Waters MS consisting of an Alliance 2795(LC) and Waters Micromass ZQ detector at 120° C. The mass spectrometerwas equipped with an electrospray ion source (ESI) operated in apositive or negative mode. The mass spectrometer was scanned betweenm/z=100-1000 with a scan time of 0.3 s.

Elemental Analysis for C, H and N composition was performed using aCostech Instrument Elemental Combustion System ECS4010 with a heliumflow of 100 mL/min (14 psi), oxygen 20 mL/min (10 psi), air 25 psi andpurge of 50 mL/min. The reported analyses are an average of two runs.

HPLC analyses were performed on a Water 600 Controller system with aWaters 717 Plus Autosampler and a Waters 2996 Photodiode Array Detector.The column used was an ACE C₁₈, 5 μm, 4.6×150 mm. A linear gradient wasapplied, starting at 95% A (A: 0.1% H₃PO₄ in water) and ending at 90% B(B: MeCN) over 6 min and then maintained at 90% B until the 10 min mark.The column was then re-equilibrated over 3 min to 95:5 with a total runtime of 20 min. The column temperature was at rt with the flow rate of1.0 mL/min. The Diode Array Detector was scanned from 200-400 nm. Forhigh purity samples requiring baseline subtraction, a linear gradientwas applied, starting at 99% A (A: 0.1% H₃PO₄ in water) and ending at90% B (B: MeCN) over 15 min. The column was then re-equilibrated over 3min to 99% A with a total run time of 23 min. The column temperature wasat rt with the flow rate of 1.0 mL/min. The Diode Array Detector wasscanned from 200-400 nm. A blank MeOH sample was run immediately priorto the sample of which purity was to be determined: this was thensubtracted to obtain the baseline subtracted chromatogram.

Thin layer chromatography (TLC) was performed on Alugram® (Silica gel 60F₂₅₄) from Mancherey-Nagel and UV was typically used to visualize thespots. Additional visualization methods were also employed in somecases. In these cases the TLC plate was developed with iodine (generatedby adding approximately 1 g of I₂ to 10 g silica gel and thoroughlymixing), vanillin (generated by dissolving about 1 g vanillin in 100 mL10% H₂SO₄), potassium permanganate (generated by dissolving 1.5 g KMnO₄and 10 g K₂CO₃ in 1.25 mL NaOH and 200 mL H₂O), ninhydrin (availablecommercially from Aldrich), or Magic Stain (generated by thoroughlymixing 25 g (NH₄)₆Mo₂O₂₄.4H₂O, 5 g (NH₄)₂Ce(IV)(NO₃)₆ in 450 mL H₂O and50 mL conc H₂SO₄) to visualize the compound. Flash chromatography waspreformed using typically 40-63 μm (230-400 mesh) silica gel fromSilicycle following analogous techniques to those disclosed by Still etal. Typical solvents used for flash chromatography or thin layerchromatography (TLC) were mixtures of CHCl₃/MeOH, CH₂Cl₂/MeOH,EtOAc/MeOH and hexane/EtOAc. Reverse phase flash chromatography wereperformed on a Biotage® using a Biotage C₁₈ cartridges and a H₂O/MeOHgradient (typically eluting from 5% MeOH/H₂O to 90% MeOH/H₂O).

Preparative chromatography was performed on either a Waters Prep LC 4000System using a Waters 2487 Diode Array or on a Waters LC Module 1 plus.The column used were either a Waters×Terra Prep C₁₈, 5 μm, 30×100 mm,Phenomenex Luna C₁₈, 5 μm, 21.6×250 mm, or a Phenomenex Gemini C₁₈, 5μm, 100×30 mm. Narrow gradients with MeCN/H₂O (water containing either0.1% TFA, 0.1% AcOH, 0.1% HCO₂H or 0.1% NH₄OAc) were used to elute thecompound at a flow rate of approximately 20 mL/min and a total run timebetween 20-30 min.

For enantiomeric excess determination, chiral HPLC analysis wasperformed on a Waters 600 Controller and Multisolvent Delivery Systemusing a Waters 717+Autosampler and a Waters 996 Photodiode ArrayDetector with a Crownpak CR(+) column, eluting with 85:15 pH 1perchloric acid in H₂O/MeOH mobile phase. The pH 1 perchloric acid wasgenerated by adding 16.3 g of 70% perchloric acid to 1 L of distilledH₂O.

Starting materials used were either available from commercial sources orprepared according to literature procedures and had experimental data inaccordance with those reported. 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol,for example, can be synthesized according to the methods described inU.S. patent application Ser. No. 12/142,692, as well as U.S. Pat. Pubs.US20060234981 and US20070155699.

EXAMPLE 1 1.5-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c]d[1,2]oxaborol-1(3H)-ol

Step 1: Preparation of methyl 4-bromo-3-methylbenzoate

A stirred suspension of 4-bromo-3-methylbenzoic acid (2.15 g, 10 mmol)in thionyl chloride (10 mL) was refluxed for 4 h, cooled to rt andconcentrated under reduced pressure. The residue was dissolved in MeOH(15 mL) and the reaction mixture was refluxed for 2 h. The mixture wascooled to rt and concentrated under reduced pressure. The residue wasdissolved in EA (10 mL), washed with water, dried over MgSO₄, filteredand concentrated under reduced pressure to give methyl4-bromo-3-methylbenzoate (2.07 g; yield 69%) as a red solid.

Step 2: Preparation of (4-bromo-3-methylphenyl)methanol

To a solution of methyl 4-bromo-3-methylbenzoate (500 mg, 2.18 mmol) inTHF (5.2 mL) at −30° C. was slowly added LiAlH₄ (83 mg, 2.18 mmol). Thereaction mixture was stirred for 15 min, quenched with a solution ofmethanol and water (4:1, 10 mL), and stirred at rt for 30 min. Themixture was neutralized with 6 N HCl to pH of 7 and extracted with ethylacetate (20 mL). The organic layer was dried over MgSO₄, filtered andconcentrated under reduced pressure to afford(4-bromo-3-methylphenyl)methanol (420 mg; yield 96%) as an oil.

Step 3: Preparation of 4-bromo-3-methylbenzaldehyde

To a solution of (4-bromo-3-methylphenyl)methanol (420 mg, 2.09 mmol) inDCM (6 mL) at rt was added MnO₂ (1.82 g, 20.9 mmol). The reactionmixture was stirred for 12 h, filtered and concentrated under reducedpressure to give 4-bromo-3-methyl-benzaldehyde (372 mg; yield 89%) as anoil.

Step 4: Preparation of 4-bromo-3-methylbenzaldehyde oxime

To a mixture of 4-bromo-3-methyl-benzaldehyde (372 mg, 1.87 mmol) andhydroxylamine hydrochloride (306.5 mg, 4.41 mmol) in ethanol (5 mL) atrt was added Et₃N (0.15 mL). The reaction mixture was heated underreflux for 2 h, cooled to rt and concentrated under reduced pressure.The residue was dissolved in EA (10 mL), washed with water, dried overMgSO₄, filtered and concentrated under reduced pressure to give4-bromo-3-methylbenzaldehyde oxime (384 mg; yield 96%) as a white solid.

Step 5 and 6: Preparation of3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

A mixture of 4-bromo-3-methylbenzaldehyde oxime (384 mg, 0.5 mmol) andNCS (286.7 mg, 2.14 mmol) in DMF (10 mL) was stirred at 40° C. for 40min. The mixture was cooled to 0° C. and to it was added1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (261 mg, 1.08mmol) followed by Et₃N (0.15 mL). The reaction mixture was stirred at rtfor 20 h, poured into water and extracted with EA (10 mL). The organiclayer was washed with water, dried over MgSO₄, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography over silica gel to give3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(364.2 mg; yield 82%) as a white solid.

Step 7: Preparation of3-(4-bromo-3-(bromomethyl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

A mixture of3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(100 mg, 0.221 mmol), NBS (62.8 mg, 0.35 mmol) and AIBN (cat.) in1,2-dichloroethane (10 mL) was refluxed for 3.5 h and concentrated underreduced pressure. The residue was purified by column chromatography oversilica gel to give crude3-(4-bromo-3-(bromomethyl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(50 mg, yield 42%) as an oil.

Step 8: Preparation of2-bromo-5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzylacetate

A solution of3-(4-bromo-3-(bromomethyl)phenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(36 mg, 0.068 mmol) and NaOAc (6 mg, 0.074 mmol) in AcOH (1 mL) wasrefluxed for 16 h, cooled to rt and concentrated under reduced pressure.The residue was dissolved in EA, washed with H₂O, dried over MgSO₄,filtered and concentrated under reduced pressure to give2-bromo-5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzylacetate (29 mg; yield 85%) as a yellow solid.

Step 9: Preparation of5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate

A mixture of2-bromo-5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)benzylacetate (25 mg, 0.05 mmol), bis(pinacolato)diboron (25 mg, 0.1 mmol),Pd(dppf)Cl₂ (4 mg, 0.005 mmol) and KOAc (15 mg, 0.15 mmol) in dry1,4-dioxane (1 mL) was stirred under N₂ at rt for 0.5 h and at 100° C.for 5 h. The reaction mixture was cooled to rt and concentrated underreduced pressure. The residue was dissolved in EA, washed with H₂O,dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by preparative TLC to give5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (24 mg; yield 89%) as a colorless oil.

Step 10: Preparation of5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3yl)benzo[c][1,2]oxaborol-1(3H)-ol

A mixture of5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (50 mg, 0.09 mmol) and LiOH H₂O (15 mg, 0.36 mmol) in THF-H₂O (1mL/0.2 mL) was stirred at rt for 1 h and diluted with EA (2 mL). Theorganic phase was dried over MgSO₄, filtered and concentrated underreduced pressure to give a residue that was dissolved in HCl-EtOH (4 N,5 mL) and H₂O (0.3 mL). The mixture was stirred at 35° C. for 20 h. Toit was added conc HCl (1.7 mL) and the reaction mixture was stirred at60° C. for 20 h. The mixture was cooled to rt, concentrated underreduced pressure. The residue was purified by preparative TLC to givethe desired title compound (10 mg; yield 27%) as a white solid. ¹H NMR(400 MHz, CDCl₃): δ 7.81 (d, J=6.8 Hz, 1H), 7.68 (s, 1H), 7.63 (d, J=8.0Hz, 1H), 7.51 (s, 2H), 7.43 (d, J=1.2 Hz, 1H), 5.13 (s, 2H), 4.12 (m,1H), 3.74 (m, 1H) ppm; MS: m/z=416 (M+1, ESI+).

2.5-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of methyl 2-bromo-5-methylbenzoate

To a solution of 2-bromo-5-methylbenzoic acid (215 mg, 1.0 mmol) in DCM(4 mL) and DMF (1 drop) at 0° C. was slowly added oxalyl chloride (0.13mL, 1.5 mmol). The reaction mixture was stirred at rt for 1 h and to itwas added additional oxalyl chloride (0.13 mL, 1.5 mmol). The reactionmixture was stirred for 1 h, added with MeOH (2 mL) and stirred for 6 h.The mixture was treated with Na₂CO₃ to pH of 9 and extracted with DCM(2×10 mL). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography over silica gel elutedwith PE-EA (15:1) to give methyl 2-bromo-5-methylbenzoate (210 mg; yield92%) as colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 7.60 (d, J=1.6 Hz,1H), 7.53 (d, J=8.8 Hz, 1H), 7.15 (q, J=3.2 Hz, 1H), 3.92 (s, 3H), 2.33(s, 3H) ppm.

Step 2: Preparation of 2-(2-bromo-5-methylphenyl)propan-2-ol

To a solution of methyl 2-bromo-5-methylbenzoate (193 mg, 0.84 mmol) inTHF (4 mL) was added dropwise MeMgBr (1.1 mL, 3.37 mmol) at 0° C. underargon and then stirred at rt for 3 h. The reaction mixture was quenchedwith saturated NH₄Cl and extracted with EA. The combined organic layerwas washed with NaHCO₃ solution and brine, dried over Na₂SO₄. Thesolution was concentrated and the residue was purified by columnchromatography over silica gel eluted with PE-EA (30:1˜20:1) to provide2-(2-bromo-5-methylphenyl)propan-2-ol (134 mg; yield 69%) as a whitesolid. ¹H NMR (400 MHz, CDCl₃): δ 7.49 (q, J=2.0 Hz, 2H), 6.94 (q, J=2.0Hz, 1H), 2.63 (s, 1H), 2.33 (s, 3H), 1.76 (s, 6H) ppm.

Step 3: Preparation of 3,3,5-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution of 2-(2-bromo-5-methylphenyl)propan-2-ol (134 mg, 0.585mmol) in THF (5 mL) at −78° C. was slowly added n-BuLi (1.1 mL, 1.75mmol). The reaction mixture was stirred for 2 h and to it was addedB(OPr-i)₃ (0.203 mL, 0.88 mmol). The reaction mixture was allowed towarm to rt and stirred at rt for 6 h. The mixture was cooled to 0° C.,treated with 3 N HCl (10 mL), stirred for 3 h and extracted with EA. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography over silica gel eluted with PE-EA (10:1-5:1) to give3,3,5-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol (27 mg; yield 26%) as acolorless oil. ¹H NMR (400 MHz, CDCl₃): δ 7.61 (d, J=7.6 Hz, 1H), 7.20(d, J=7.2 Hz, 1H,), 7.09 (s, 1H), 2.44 (s, 3H), 1.56 (s, 6H) ppm.

Step 4: Preparation of1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde

To a solution of 3,3,5-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol (27 mg,0.153 mmol) in CCl₄ (2 mL) at rt was added benzoyl peroxide (3.7 mg,0.0153 mmol) followed by NBS (60 mg, 0.337 mmol). The reaction mixturewas heated under reflux for 12 h, cooled to rt and treated with Na₂CO₃.The aqueous layer was acidified with 3 N HCl to pH of 3 and extractedwith EA. The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by prep-TLC to give1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde(12 mg; yield 41%) as white solid. ¹H NMR (400 MHz, CDCl₃): δ 10.12 (s,1H), 7.88 (s, 2H), 7.80 (s, 1H), 1.62 (s, 6H) ppm.

Step 5: Preparation of1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehydeoxime

To a solution of1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde(10 mg, 0.053 mmol) and NH₂OH.HCl (4.4 mg, 0.063 mmol) in THF (4 mL) andH₂O (1 mL) at rt was added NaOAc(6 mg, 0.074 mmol). The reaction mixturewas stirred for 3 h and diluted with H₂O. The mixture was extracted withEA and the organic layer was separated. The organic solution was washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by prep-TLC to provide1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehydeoxime (8 mg; yield 74%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ8.23 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.55 (m, 2H), 2.81 (s, 1H,), 1.61(s, 6H) ppm.

Step 6: Preparation ofN,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride

To a solution of1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehydeoxime (8 mg, 0.039 mmol) in DMF (1.0 mL) at rt was added NCS (6.2 mg,0.047 mmol). The reaction mixture was stirred for 2 h, warmed to 40° C.and stirred for 3 h. The mixture was cooled to rt, poured into ice-water(10 mL) and extracted with EA (20 mL). The organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure to giveN,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (8 mg; yield 86%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ12.50 (s, 1H), 7.90 (s, 1H), 7.70-7.79 (m, 2H), 1.61 (s, 6H) ppm.

Step 7: Preparation of1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene

A mixture of 3,5-dichlorophenylboronic acid (5 g, 26.2 mmol),2-bromo-3,3,3-trifluoroprop-1-ene (5 g, 28.6 mmol), K₂CO₃ (7.24 g, 52.4mmol) and Pd(PPh₃)₂Cl₂ (368 mg) in THF (20 mL) and H₂O (10 mL) washeated at 70° C. in a sealed tube for 4 h. The mixture was cooled to rtand partitioned between ether (50 mL) and H₂O (50 mL). The aqueous layerwas extracted with ether (50 mL) and the combined organic layers weredried over Na₂SO₄. The solvent was removed under reduced pressure andthe crude product was purified by column chromatography over silica geleluted with hexanes to afford1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (5.77 g; yield85%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.42 (t, J=2.0 Hz,2H), 7.34 (d, J=2.0 Hz, 1H), 6.05 (s, 1H), 5.82 (s, 1H) ppm.

Step 8: Preparation of5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol

To a solution ofN,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (8 mg, 0.033 mmol) and1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (8.9 mg, 0.0367mmol) in DMF (1 mL) at rt was added TEA (5.1 μL, 0.0367 mmol). Thereaction mixture was stirred for 12 h, poured into ice-water andextracted with EA (10 mL). The organic layer was washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by prep-TLC to give the title compound5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol(9.5 mg; yield 64%) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆):δ 9.26 (s, 1H), 7.66-7.85 (m, 6H), 4.32-4.96 (m, 2H), 1.51 (s, 6H) ppm;MS: m/z=444 (M+1, ESI+).

3.(S)-5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

The title compound was obtained by separation of the racemic mixture of5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-olwith chiral column chromatography. MS: m/z=444 (M+1, ESI+). The racemicmixture was dissolved in the solvent of mobile phase and separated bysupercritical fluid (SFC) chiral chromatography. The chromatographyconditions used were: column CHIRALCEL OJ-H (column size: 0.46 cmI.D.×15 cm length), mobile phase CO₂/MeOH=70/30 (w/w), flow rate 2.0mL/min, detector wave length UV 220 nm, and temperature 35° C.

4.(R)-5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

The title compound was obtained by separation of the racemic mixture of5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-olwith chiral column chromatography. MS: m/z=444 (M+1, ESI+). The racemicmixture was dissolved in the solvent of mobile phase and separated bysupercritical fluid (SFC) chiral chromatography. The chromatographyconditions used were: column CHIRALCEL OJ-H (column size: 0.46 cmI.D.×15 cm length), mobile phase CO₂/MeOH=70/30 (w/w), flow rate 2.0mL/min, detector wave length UV 220 nm, and temperature 35° C.

5.5-(5-(3,5-Dibromophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of1,3-dibromo-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene

A mixture of 3,5-dibromophenylboronic acid (2.58 g, 9.2 mmol),2-bromo-3,3,3-trifluoroprop-1-ene (2.42 g, 13.8 mmol), K₂CO₃ (2.54 g,18.4 mmol) and Pd(PPh₃)₂Cl₂ (129 mg, 0.18 mmol) in THF (12 mL) and H₂O(6 mL) was heated at 80° C. in a sealed tube for 4 h. The mixture wascooled to rt and partitioned between EA (50 mL) and H₂O (50 mL). Theaqueous layer was extracted with EA (50 mL) and the combined organiclayers were dried over Na₂SO₄. The solvent was removed under reducedpressure and the crude product was purified by column chromatography onsilica gel to give the crude desired product (2.3 g; 76% yield) ascolorless oil.

Step 2: Preparation of5-(5-(3,5-dibromophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution of(Z)—N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (850 mg, 3.55 mmol) and1,3-dibromo-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (1.75 g, 5.32 mmol)in DMF (10 mL) at rt was added TEA (0.5 mL, 3.55 mmol). The reactionmixture was stirred at rt for 18 h, poured into ice-water and extractedwith EA (20 mL). The organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography to give the desired title compound5-(5-(3,5-dibromophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol(600 mg; 32% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.22(s, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.79 (m, 4H), 7.73 (dd, J=8.0 Hz, 0.8Hz, 1H), 4.45 (d, J=18.8 Hz, 1H), 4.33 (d, J=18 Hz, 1H), 1.50 (d, J=2.8Hz, 6H) ppm; HPLC purity: 100% at 220 nm and 100% at 254 nm; MS:m/z=534.0 (M+1, ESI+).

6.5-(5-(3-Chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

The title compound was prepared by using the same method as described in5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-olwith1-chloro-3-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene toreplace 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene. It wasobtained as a white solid. MS: m/z=478.1 [M+1]⁺.

7.3,3-Dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene

A mixture of 3,4,5-trichlorophenylboronic acid (3.376 g, 15 mmol),2-bromo-3,3,3-trifluoroprop-1-ene (4.02 g, 23 mmol), K₂CO₃ (4.15 g, 30mmol) and Pd(PPh₃)₂Cl₂ (4.15 g, 30 mmol) in THF (16 mL) and H₂O (8 mL)was heated at 80° C. in a sealed tube for 4 h. The mixture was cooled tort and partitioned between EA (50 mL) and H₂O (50 mL). The aqueous layerwas extracted with EA (50 mL) and the combined organic layers were driedover anhydrous Na₂SO₄. The solvent was removed under reduced pressureand the crude product was purified by column chromatography on silicagel to give the crude desired product (3.7 g; 90% yield) as a paleyellow solid.

Step 2: Preparation of1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehydeoxime

To a mixture of1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde(560 mg, 2.95 mmol) and NH₂OH.HCl (246 mg, 3.54 mmol) in THF (6 mL) andH₂O (1.5 mL) at rt was added NaOAc (339 mg, 4.13 mmol). The reactionmixture was stirred at rt for 16 h, diluted with H₂O and extracted withEA (10 mL×2). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure to givethe desired product (620 mg, 100% yield) as a white solid.

Step 3: Preparation of(Z)—N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride

To a solution of1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehydeoxime (1.38 g, 6.73 mmol) in DMF (15 mL) at rt was added NCS (1.07 g,8.03 mmol). The reaction mixture was warmed to 45° C., stirred for 3 hand cooled to rt. The mixture was poured into ice-water (20 mL) andextracted with EA (20 mL×2). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give the desired product (1.7 g; 100% yield) as a whitesolid.

Step 4: Preparation of3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol

To a solution ofN,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (850 mg, 3.55 mmol) and1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (1.47 g, 5.32mmol) in DMF (10 mL) at rt was added TEA (0.5 mL, 3.55 mmol). Thereaction mixture was stirred at rt for 18 h, poured into ice-water andextracted with EA (20 mL). The organic layer was washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography to give the desired titlecompound3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol(510 mg; 30% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.25(s, 1H), 7.86 (s, 2H), 7.78 (s, 2H), 7.72 (d, J=7.2 Hz, 1H), 4.46 (d,J=19.2 Hz, 1H), 4.35 (d, J=18.4 Hz, 1H), 1.49 (s, 6H) ppm; HPLC purity:95.3% at 220 nm and 96.8% at 254 nm; MS: m/z=478.4 (M+, ESI+).

8.5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of2-(3,5-dichloro-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

4,4,4′,4′,5,5,5′,5′-Octamethyl[2,2′-bi-1,3,2-dioxaborolane] (2.0 g, 7.88mmol), 2,6-bis(1-methylethyl)-N-(2-pyridinylmethylene)benzenamine (0.080g, 0.30 mmol), and bis(1,5-cyclooctadiene)diiridium dichloride (0.132 g,0.20 mmol) were added to a solution of 1,3-dichloro-2-fluorobenzene (2.0g, 12.12 mmol) in heptane (40 mL). The reaction mixture turned fromyellow to forest green to brick red within the first minute. Thereaction mixture was refluxed for 18 h. The mixture was then partitionedbetween EA and water, and the aqueous extract was washed twice with EA.The organic extracts were combined, dried over Na₂SO₄, and concentratedunder reduced pressure. The solid residue was purified by chromatographyon silica gel eluted with PE-EA (10:1) to give2-(3,5-dichloro-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.56 g, yield 72.5%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 7.646(d, J=6.5 Hz, 2H), 1.266 (s, 12H) ppm.

Step 2: Preparation of1,3-dichloro-2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene

A mixture of2-(3,5-dichloro-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.56 g, 8.83 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (1.85 g, 10.6mmol), Cs₂CO₃ (11.5 mL, 2M, 17.7 mmol) and Pd(PPh₃)₂Cl₂ (200 mg) in THF(30 mL) was heated at 70° C. in a sealed tube for 4 h. The mixture wascooled to rt and partitioned between ether and H₂O. The aqueous layerwas extracted with EA and the combined organic layers were dried overNa₂SO₄. The solvent was removed under reduced pressure and the crudeproduct was purified by column chromatography on silica gel eluted withhexanes to give1,3-dichloro-2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (1.3 g;yield 56%) as colorless oil. ¹H NMR (500 MHz, CDCl₃): δ 7.412 (d, J=6.5Hz, 2H), 6.057 (s, 1H), 5.806 (s, 1H) ppm.

Step 3: Preparation of5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol

To a solution of the crude compoundN,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (383 mg, 1.60 mmol) and1,3-dichloro-2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (455 mg,1.76 mmol) in DMF (12 mL) at rt was added TEA (445 μL, 3.20 mmol). Thereaction mixture was stirred for 12 h, poured into ice-water andextracted with EA. The organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-TLC eluted with PE-EA (3:2) and then purified bycombiflash to give the title compound5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol(180 mg; yield 24% over the 3 steps from the aldehyde) as a white solid.¹H NMR (500 MHz, DMSO-d₆): δ 9.236 (s, 1H), 7.803 (d, J=6.5 Hz, 2H),7.757-7.770 (m, 2H), 7.693-7.710 (m, 1H), 4.414 (d, J=18.0 Hz, 1H),4.316 (d, J=18.0 Hz, 1H), 1.481 (s, 6H) ppm; HPLC purity: 99.13% at 220nm and 99.15% at 254 nm; MS: m/z=461.9 (M+1, ESI+).

9.5-(5-(3,5-Dichloro-4-methylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

Preparation of 1,3-dichloro-5-iodo-2-methylbenzene

To the mixture of LDA (5 mL, 8.6 mmol) in THF (20 mL) was added compound1,3-dichloro-5-iodobenzene (2.35 g, 8.6 mmol) under −78° C. Then themixture was added to the pre-cooled solution of (CH₃)₂SO₄ (12 mL, 10.3mmol) in THF (10 mL) under −78° C. The solution was concentrated undervacuum. The residue was diluted with EA, washed with 1N HCl, 1N NaOH,brine, dried over Na₂SO₄, concentrated under vacuum to give the desiredproduct (2.3 g, 93% yield).

Preparation of2-(3,5-dichloro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The mixture of 1,3-dichloro-5-iodo-2-methylbenzene (287 mg, 10 mmol),KOAc (294 mg, 3.0 mmol), Pin₂B₂ (280 mg, 1.1 mmol) and Pd(dppf)Cl₂ (73mg, 0.1 mmol) in DMF (5 mL) was stirred at 80° C. for 1 h. It waspartitioned between EA and H₂O. The organic layer was washed with H₂O,brine, dried over Na₂SO₄, concentrated under vacuum. The residue waspurified by column chromatography to give the desired product (179 mg,62% yield).

Preparation of1,3-dichloro-2-methyl-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene

The mixture of2-(3,5-dichloro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(160 mg, 0.56 mmol), K₂CO₃ (232 mg, 1.68 mmol), compound2-bromo-3,3,3-trifluoroprop-1-ene (146 mg, 0.84 mmol) and Pd(PPh₃)₂Cl₂(39 mg, 0.1 mmol) in THF/H₂O (2/1 mL) was stirred in a sealed tube at80° C. for 3 h. It was partitioned between EA and H₂O. The organic layerwas washed with brine, dried over Na₂SO₄, concentrated under vacuum. Theresidue was purified by column chromatography to give the desiredproduct (78 mg, 55% yield).

Preparation of5-(5-(3,5-dichloro-4-methylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

The mixture of(E)-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehydeoxime (62 mg, 0.3 mmol) and NCS (48 mg, 0.36 mmol) in DMF (2 mL) wasstirred at rt overnight. To the mixture was added1,3-dichloro-2-methyl-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (75 mg,0.3 mmol) and Et₃N (0.1 mL) and the mixture was stirred at rt for 4 h.It was partitioned between EA and H₂O. The organic layer was washed withH₂O, brine, dried over Na₂SO₄, concentrated under vacuum. The residuewas purified to give the desired product (30 mg, 21.8% yield). ¹H NMR(400 MHz, DMSO-d₆): δ 9.20 (s, 1H), 7.77-7.70 (m, 3H), 7.63 (s, 2H),4.42 (d, J=18.4 Hz, 1H), 4.30 (d, J=18.4 Hz, 1H), 2.45 (s, 3H), 1.48 (d,J=2.4 Hz, 6H), ppm; HPLC purity: 98.6% at 220 nm and 98.9% at 254 nm;MS: m/z=458.5 (M+1, ESI+).

10.5-(5-(3,5-Dichloro-4-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of2-(3,5-dichloro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

4,4,4′,4′,5,5,5′,5′-Octamethyl[2,2′-bi-1,3,2-dioxaborolane] (0.50 g,1.97 mmol), 2,6-bis(1-methylethyl)-N-(2-pyridinylmethylene)benzenamine(0.020 g, 0.075 mmol), and bis(1,5-cyclooctadiene)diiridium dichloride(0.033 g, 0.049 mmol) were added to a solution of1,3-dichloro-2-(trifluoromethyl)benzene (0.65 g, 3.02 mmol) in heptane(10 mL). The reaction mixture turned from yellow to forest green tobrick red within the first minute. The reaction mixture was refluxed for18 h. The mixture was then partitioned between EA and water, and theaqueous extract was washed twice with EA. The organic extracts werecombined, dried over Na₂SO₄, and concentrated under reduced pressure.The solid residue was purified by chromatography on silica gel elutedwith PE-EA (8:1) to give2-(3,5-dichloro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.89 g, yield 86%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 7.721(s, 2H), 1.278 (s, 12H) ppm.

Step 2: Preparation of1,3-dichloro-2-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene

A mixture of2-(3,5-dichloro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.62 g, 1.8 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (0.38 g, 2.16mmol), Cs₂CO₃ (1.8 mL, 2M, 3.6 mmol) and Pd(PPh₃)₂Cl₂ (38 mg) in THF (10mL) was heated at 70° C. in a sealed tube for 4 h. The mixture wascooled to rt and partitioned between ether and H₂O. The aqueous layerwas extracted with EA and the combined organic layers were dried overNa₂SO₄. The solvent was removed under reduced pressure and the crudeproduct was purified by column chromatography on silica gel eluted withhexanes to give1,3-dichloro-2-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene(0.295 g; yield 53%) as colorless oil. ¹H NMR (500 MHz, CDCl₃): δ 7.433(s, 2H), 6.073 (s, 1H), 5.846 (s, 1H) ppm.

Step 3: Preparation of5-(5-(3,5-dichloro-4-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol

To a solution of crudeN,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (93 mg, 0.39 mmol) and1,3-dichloro-2-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene(133 mg, 0.43 mmol) in DMF (5 mL) at rt was added TEA (60 μL, 0.43mmol). The reaction mixture was stirred for 12 h, poured into ice-waterand extracted with EA. The organic layer was washed with brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by prep-TLC eluted with PE-EA (3:2) and thenpurified by combiflash to give the title compound5-(5-(3,5-dichloro-4-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol(50 mg; yield 25% over 3 steps) as a white solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.220 (s, 1H), 7.837 (s, 2H), 7.716-7.731 (m, 2H),7.650-7.666 (m, 1H), 4.423 (d, J=18.0 Hz, 1H), 4.311 (d, J=18.0 Hz, 1H),1.432 (s, 6H) ppm; HPLC purity: 99.3% at 220 nm and 99.4% at 254 nm.

11.5-(5-(3,5-Dichloro-4-(difluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of 1,3-dichloro-2-(difluoromethyl)benzene

Compound 2,6-dichlorobenzaldehyde (3.94 g, 22.5 mmol) was placed in aTeflon-coated flask and dissolved in DCM (200 mL). BAST (9.96 g, 45mmol) was slowly added and the reaction mixture was stirred at rtovernight. The reaction mixture was then slowly added to a vigorouslystirring NaHCO₃-saturated aqueous solution (400 mL) under cooling withice. After 1 h the phases were separated and the aqueous layer wasextracted with DCM three times. The combined organic layers were washedtwice with water, dried over Na₂SO₄, filtered and evaporated to dryness.The residue was purified by column chromatography on silica gel elutedwith PE-EA (15:1) to give 1,3-dichloro-2-(difluoromethyl)benzene (3.56g; yield 80%) as colorless oil. ¹H NMR (500 MHz, CDCl₃): δ 7.044 (t,J=53.5 Hz, 1H), 7.207 (m, 3H) ppm.

Step 2: Preparation of2-(3,5-dichloro-4-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

4,4,4′,4′,5,5,5′,5′-Octamethyl[2,2′-bi-1,3,2-dioxaborolane] (0.91 g,3.56 mmol), 2,6-bis(1-methylethyl)-N-(2-pyridinylmethylene)benzenamine(0.036 g, 0.135 mmol), and bis(1,5-cyclooctadiene)diiridium dichloride(0.06 g, 0.089 mmol) were added to a solution of1,3-dichloro-2-(difluoromethyl)benzene (1.08 g, 5.48 mmol) in heptane(18 mL). The reaction mixture turned from yellow to forest green tobrick red within the first minute. The reaction mixture was refluxed for18 h. The mixture was then partitioned between EA and water, and theaqueous extract was washed twice with EA. The organic extracts werecombined, dried over Na₂SO₄, and concentrated under reduced pressure.The solid residue was purified by chromatography on silica gel elutedwith PE-EA (8:1) to give2-(3,5-dichloro-4-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.30 g, yield 73%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 7.678(s, 2H), 7.061 (t, J=52.5 Hz, 1H), 1.275 (s, 12H) ppm.

Step 3: Preparation of1,3-dichloro-2-(difluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene

A mixture of2-(3,5-dichloro-4-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane(0.58 g, 1.8 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (0.45 g, 2.5mmol), Cs₂CO₃ (1.8 mL, 2M, 3.6 mmol) and Pd(PPh₃)₂Cl₂ (38 mg) in THF (10mL) was heated at 70° C. in a sealed tube for 4 h. The mixture wascooled to rt and partitioned between ether and H₂O. The aqueous layerwas extracted with EA and the combined organic layers were dried overNa₂SO₄. The solvent was removed under reduced pressure and the crudeproduct was purified by column chromatography on silica gel eluted withhexanes to give1,3-dichloro-2-(difluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene(0.33 g; yield 62%) as colorless oil. ¹H NMR (500 MHz, CDCl₃): δ 7.381(s, 2H), 7.045 (t, J=53.0 Hz, 1H), 6.049 (s, 1H), 5.820 (s, 1H) ppm.

Step 4: Preparation of5-(5-(3,5-dichloro-4(difluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol

To a solution of crudeN,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (156 mg, 0.65 mmol) and1,3-dichloro-2-(difluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene(210 mg, 0.72 mmol) in DMF (8 mL) at rt was added TEA (100 μL, 0.72mmol). The reaction mixture was stirred for 12 h, poured into ice-waterand extracted with EA. The organic layer was washed with brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by prep-TLC eluted with PE-EA (3:2) and thenpurified by combiflash to give the title compound5-(5-(3,5-dichloro-4(difluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol(90 mg; yield 28% over 3 steps) as a white solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.268 (s, 1H), 7.796 (s, 2H), 7.757-7.771 (m, 2H),7.694-7.710 (m, 1H), 7.389 (t, J=52.0 Hz, 1H), 4.451 (d, J=18.0 Hz, 1H),4.344 (d, J=18.0 Hz, 1H), 1.476 (s, 6H); HPLC purity: 99.28% at 220 nmand 100% at 254 nm; MS: m/z=494.0 (M+1, ESI+).

12.5-(5-(3,5-Dichloro-4-(trifluoromethoxy)phenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of 2,6-diisopropyl-N-(pyridin-2-ylmethylene)aniline

2,6-Diisopropylaniline (2.0 g, 11.3 mmol) was added to a solution ofpicolinaldehyde (1.2 g, 11.3 mmol) in toluene (200 mL) in a round bottomflask equipped with a Dean-Stark trap, followed by the addition of acatalytic amount of p-toluenesulfonic acid (0.1 g). The reaction mixturewas refluxed for 18 h to remove water. The reaction mixture was cooledto rt, and then washed once with water (100 mL), and the toluene wasremoved under reduced pressure. The resulting residue was purified bychromatography on silica gel to give the desired product (1.2 g, 40%yield) as a pale green solid.

Step 2: Preparation of2-(3,5-dichloro-4-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.0 g, 7.88mmol), 2,6-diisopropyl-N-(pyridin-2-ylmethylene)aniline (40 mg, 0.15mmol), and bis(1,5-cyclooctadiene)diiridium dichloride (C₁₆H₂₄Cl₂Ir₂, 61mg, 0.10 mmol) were added to a solution of1,3-dichloro-2-(trifluoromethoxy)benzene (1.37 g, 11.81 mmol) inn-heptane (20 mL). The reaction mixture was refluxed for 3 h. Thereaction mixture was then partitioned between EA and water, and theaqueous layer extract twice with EA. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatography togive the desired product (1.2 g, 28.5% yield) as white solid.

Step 3: Preparation of1,3-dichloro-2-(trifluoromethoxy)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene

A mixture of2-(3,5-dichloro-4-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.2 g, 3.36 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (647 mg, 3.70mmol), K₂CO₃ (927 mg, 6.72 mmol) and Pd(PPh₃)₂Cl₂ (47.2 mg, 0.067 mmol)in THF (10 mL) and H₂O (6 mL) was heated at 80° C. in a sealed tube for4 h. The mixture was cooled to rt and partitioned between EA (50 mL) andH₂O (50 mL). The aqueous layer was extracted with EA (50 mL) and thecombined organic layers were dried over Na₂SO₄. The solvent was removedunder reduced pressure and the crude product was purified by columnchromatography on silica gel to give the crude desired product (780 mg;72% yield) as colorless oil.

Step 4: Preparation of5-(5-(3,5-dichloro-4-(trifluoromethoxy)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution of(Z)—N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (378 mg, 1.58 mmol) and1,3-dichloro-2-(trifluoromethoxy)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene(567 mg, 1.74 mmol) in DMF (10 mL) at rt was added TEA (176 mg, 1.74mmol). The reaction mixture was stirred at rt for 18 h, poured intoice-water and extracted with EA (20 mL). The organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography to give thefinal desired title compound5-(5-(3,5-dichloro-4-(trifluoromethoxy)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol(310 mg; 37% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.22(s, 1H), 7.91 (s, 2H), 7.76 (d, J=7.6 Hz, 2H), 7.70 (d, J=8.4 Hz, 1H),4.46 (d, J=18.4 Hz, 1H), 4.37 (d, J=18.0 Hz, 1H), 1.48 (s, 6H) ppm; HPLCpurity: 97.1% at 220 nm and 99.0% at 254 nm; MS: m/z=528.4 (M+, ESI+).

13.5-(5-(3,5-Dichlorophenyl)-5-(perfluoroethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of1,3-dichloro-5-(3,3,4,4,4-pentafluorobut-1-en-2-yl)benzene

A mixture of 3,5-dichlorophenylboronic acid (793 mg, 4.15 mmol),2-bromo-3,3,4,4,4-pentafluorobut-1-ene (1.0 g, 4.57 mmol), K₂CO₃ (1.14g, 8.3 mmol) and Pd(PPh₃)₂Cl₂ (58 mg, 0.08 mmol) in THF (4 mL) and H₂O(2 mL) was heated at 80° C. in a sealed tube for 4 h. The mixture wascooled to rt and partitioned between EA (50 mL) and H₂O (50 mL). Theaqueous layer was extracted with EA (50 mL) and the combined organiclayers were dried over Na₂SO₄. The solvent was removed under reducedpressure and the crude product was purified by column chromatography onsilica gel to give the crude desired product (800 mg; 66% yield) ascolorless oil.

Step 2: Preparation of3,3-dimethyl-5-(5-(3,5-dichlorophenyl)-5-(perfluoroethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol

To a solution ofN,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (378 mg, 1.58 mmol) and1,3-dichloro-5-(3,3,4,4,4-pentafluorobut-1-en-2-yl)benzene (506 mg, 1.74mmol) in DMF (5 mL) at rt was added TEA (176 mg, 1.74 mmol). Thereaction mixture was stirred at rt for 18 h, poured into ice-water andextracted with EA (20 mL). The organic layer was washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography to give the final desiredtitle compound5-(5-(3,5-dichlorophenyl)-5-(perfluoroethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol(180 mg; 23% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.22(s, 1H), 7.82 (s, 2H), 7.77-7.70 (m, 3H), 7.60 (s, 1H), 4.55 (d, J=18.4Hz, 1H), 4.32 (d, J=17.2 Hz, 1H), 1.48 (s, 6H) ppm; HPLC purity: 97.7%at 220 nm and 99.5% at 254 nm; MS: m/z=496.3 (M+, ESI+).

14.5-(5-(3,5-Bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of1,3-bis(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene

A mixture of 3,5-bis(trifluoromethyl)phenylboronic acid (2.2 g, 8.5mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (1.79 g, 10.2 mmol),Pd(PPh₃)₂Cl₂ (179 mg, 0.26 mmol), K₂CO₃ (2.35 g, 17 mmol), and Cu₂O (37mg, 0.26 mmol) in THF (6 mL) and H₂O (3 mL) in a tube sealed under N₂was heated at 80° C. for 4 h, cooled to rt and partitioned between EAand water, extracted with EA (3×20 mL). The combined organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatography oversilica gel eluted with PE to afford1,3-bis(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene(1.5 g,yield 55%) as oil.

Step 2: Preparation of5-(4-(3,5-bis(trifluoromethyl)phenyl)-4-(trifluoromethyl)-4,5-dihydro-isoxazol-5-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

To a mixture of1,3-bis(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (400mg, 1.67 mmol),N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (770 mg, 2.51 mmol) in DMF (3 mL) was added TEA (169 mg, 1.67mmol). The mixture was stirred at rt for 12 h, quenched with water,extracted with EA (3×20 mL). The combined organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by prep-HPLC to afford5-(4-(3,5-bis(trifluoromethyl)phenyl)-4-(trifluoromethyl)-4,5-dihydroisoxazol-5-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol(200 mg, yield 26%) as solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.22 (s, 1H),8.35 (s, 1H), 8.21 (s, 1H), 7.77 (s, 1H), 7.75 (s, 1H), 7.72 (s, 1H),4.58-4.42 (q, J=18 Hz, 2H), 1.48 (s, 6H) ppm; MS: m/z=512.5 (M+1, ESI+).

15.5-(5-(3,5-Dichloro-4-(2,2,2-trifluoroethoxy)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of 1,3-dichloro-2-iodo-5-nitrobenzene

2,6-Dichloro-4-nitroaniline (20.0 g, 97.7 mmol) was reacted with NaNO₂in HCl (6N) at 0° C. Then the mixture was added to aqueous KI solution.The crude product was purified by column chromatography over silica geleluted with PE to give the desired product (12.0 g, 33% yield) as paleyellow solid.

Step 2: Preparation of1,3-dichloro-5-nitro-2-(2,2,2-trifluoroethoxyl)benzene

A Mixture of Cs₂CO₃ (17.22 g, 52.84 mmol), CuBr (361 mg, 2.52 mmol) andethyl 2-oxocyclohexanecarboxylate (856 mg, 5.03 mmol) in DMSO (30 mL)under N₂ was stirred for 0.5 h at rt. Then a solution of1,3-dichloro-2-iodo-5-nitrobenzene (8.0 g, 25.16 mmol) and2,2,2-trifluoroethanol (3.02 g, 30.19 mmol) in DMSO (20 mL) was added toit. The reaction mixture was stirred at 80° C. for 18 h and cooled toroom temperature, and then directly passed through celite. After rinsedwith 250 ml of EA, the combined filter was washed by brine, dried overanhydrous Na₂SO₄, concentrated under reduced pressure. The residue waspurified by column chromatography over silica gel eluted with PE:EA(100:1) to provide1,3-dichloro-5-nitro-2-(2,2,2-trifluoroethoxyl)benzene (1.93 g, yield12.6%) as pale yellow solid.

Step 3: Preparation of 3,5-dichloro-4-(2,2,2-trifluoroethoxy)aniline

To a solution of 1,3-dichloro-5-nitro-2-(2,2,2-trifluoroethoxyl)benzene(1.90 g, 6.55 mmol) in MeOH (20 mL) and 12 N HCl (20 mL) at rt, SnCl₂(3.72 g, 19.66 mmol) was slowly added to it and then the reactionmixture was stirred overnight at rt. To the reaction mixture was slowlyadded 3N NaOH to pH=10 and then extracted with EA. The combined organiclayers were washed with brine, dried over anhydrous Na₂SO₄, andconcentrated under reduced pressure. The residue was purified by columnchromatography over silica gel eluted with PE:EA (6:1) to provide3,5-dichloro-4-(2,2,2-trifluoroethoxy)aniline (1.60 g, yield 94%) aspale yellow oil.

Step 4: Preparation of 1,3-dichloro-2-(2,2,2-trifluoroethoxyl)benzene

3,5-Dichloro-4-(2,2,2-trifluoroethoxy)aniline(1.60 g, 6.15 mmol) in THF(20 mL) was added isopentyl nitrite (2.94 g, 17.22 mmol) dropwise. Theresulting solution was refluxed for 6 h and the solvent was removedunder reduced pressure. The residue was purified by columnchromatography over silica gel eluted with PE to provide1,3-dichloro-2-(2,2,2-trifluoroethoxyl)benzene as colorless oil.

Step 5: Preparation of2-(3,5-dichloro-4-(2,2,2-trifluoroethoxyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi(1,3,2-dioxaborolane) (925 mg,3.65 mmol), 2,6-diisopropyl-N-(pyridin-2-ylmethylene)aniline (36.5 mg,0.137 mmol), and bis(1,5-cyclooctadiene)-diiridium dichloride(C₁₆H₂₄Cl₂Ir₂, 61.3 mg, 0.091 mmol) were added to a solution of1,3-dichloro-2-(2,2,2-trifluoroethoxyl)benzene (1.34 g, 2.35 mmol) inn-heptane (30 mL). The reaction mixture was refluxed for 3 h. Thereaction mixture was then partitioned between EA and water, and theaqueous layer was extracted twice with EA. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography over silica gel eluted with PE:EA(100:1) to give2-(3,5-dichloro-4-(2,2,2-trifluoroethoxyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(530 mg, yield 39.2%) as white solid.

Step 6: Preparation of1,3-dichloro-2-(2,2,2-trifluoroethoxy)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene

A mixture of2-(3,5-dichloro-4-(2,2,2-trifluoroethoxyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(530 mg, 1.43 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (275 mg, 1.57mmol), K₂CO₃ (395 mg, 2.86 mmol) and Pd(PPh₃)₂Cl₂ (20 mg, 0.029 mmol) inTHF (3 mL) and H₂O (3 mL) was heated at 80° C. in a sealed tube for 3 h.The mixture was cooled to rt and partitioned between EA (50 mL) and H₂O(50 mL). The aqueous layer was extracted with EA (50 mL) and thecombined organic layers were dried over Na₂SO₄. The solvent was removedunder reduced pressure and the crude product was purified by columnchromatography on silica gel elute with PE to give1,3-dichloro-2-(2,2,2-trifluoroethoxy)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene(360 mg; yield 74%) as colorless oil.

Step 7: Preparation of5-(5-(3,5-dichloro-4-(2,2,2-trifluoroethoxyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution of(Z)—N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (253 mg, 1.06 mmol) and1,3-dichloro-2-(2,2,2-trifluoroethoxy)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene(360 mg, 1.06 mmol) in DMF (10 mL) at rt was added TEA (107 mg, 1.06mmol). The reaction mixture was stirred at rt for 18 h, poured intoice-water and extracted with EA (20 mL). The organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography over silicagel eluted with PE:EA (6:1) to give the final title compound (105 mg;yield 18.3%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.20 (s,1H), 7.76-7.69 (m, 5H), 4.80 (q, J=8.8 Hz, 2H), 4.37 (q, J=18.4 Hz, 2H),1.48 (s, 6H) ppm; HPLC purity: 96.2% at 220 nm and 98.3% at 254 nm; MS:m/z=542.2 (M+, ESI+).

16.3,3-Dimethyl-5-(5-methyl-5-(3,4,5-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of 1,2,3-trichloro-5-(prop-1-en-2-yl)benzene

To a mixture of 5-bromo-1,2,3-trichlorobenzene (3.64 g, 14 mmol),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (2.5 g, 15mmol) and Pd(PPh₃)₂Cl₂ (983 mg, 1.4 mmol) in THF (50 ml) and H₂O (5 ml)at rt was added K₂CO₃ (5.8 g, 42 mmol). The mixture was refluxedovernight and then concentrated under reduced pressure. The residue waspurified by column chromatography over silica gel eluted with PE:EA (5:1to 2:1) to give the desired intermediate (2.5 g, yield 81%) as a yellowoil: ¹H NMR (300 MHz, CDCl₃): δ 7.44 (s, 2H), 5.39 (s, 1H), 5.19-5.18(t, 1H), 2.10 (s, 3H) ppm.

Step 2: Preparation of3,3-dimethyl-5-(5-methyl-5-(3,4,5-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol

To a solution of(E)-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehydeoxime (500 mg, 2.44 mmol) in DMF (10 mL) at rt was added NCS (392 mg,2.93 mmol). The reaction mixture was warmed to 45° C., stirred for 2.5 hand cooled to rt. To a solution of1,2,3-trichloro-5-(prop-1-en-2-yl)benzene (277 mg, 1.26 mmol) and TEA(140.4 mg, 1.39 mmol) in DMF (15 mL) was added the above mixturedropwise at 0° C. The mixture was stirred at this temperature for 1 hand then at rt overnight. The mixture was acidified with HCl (3 N) to pHof 2 and then poured into water followed by extraction with EA (100ml×2). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-TLC eluted with PE:EA (2:1) to give the final titlecompound (200 mg, yield 37.5%) as a white solid: ¹H NMR (300 MHz,DMSO-d₆): δ 9.14 (s, 1H), 7.73-7.62 (m, 5H), 3.79-3.63 (q, 2H), 1.75 (s,3H), 1.46 (s, 6H). MS: m/z=424[M+H]+.

17.(S)-3,3-Dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol

The title compound was obtained by separation of the racemic mixture of3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-olwith chiral column chromatography. The racemic mixture was dissolved inthe solvent of mobile phase and separated by supercritical fluid (SFC)chiral chromatography. The chromatography conditions used were: columnCHIRALCEL OJ-H (column size: 0.46 cm I.D.×15 cm length), mobile phaseCO₂/MeOH=70/30 (w/w), flow rate 2.0 mL/min, detector wave length UV 220nm, and temperature 35° C.

18.(R)-3,3-Dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol

The title compound was obtained by separation of the racemic mixture of3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-olwith chiral column chromatography. The racemic mixture was dissolved inthe solvent of mobile phase and separated by supercritical fluid (SFC)chiral chromatography. The chromatography conditions used were: columnCHIRALCEL OJ-H (column size: 0.46 cm I.D.×15 cm length), mobile phaseCO₂/MeOH=70/30 (w/w), flow rate 2.0 mL/min, detector wave length UV 220nm, and temperature 35° C.

19.5-(5-(3-Chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of2-chloro-1-fluoro-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene

A mixture of (3-chloro-4-fluorophenyl) boronic acid (300 mg, 1.72 mmol),2-bromo-3,3,3-trifluoroprop-1-ene (331 mg, 1.89 mmol), K₂CO₃ (474 mg,3.44 mmol) and Pd(PPh₃)₂Cl₂ (25 mg, 0.035 mmol) in THF (2 mL) and H₂O (1mL) was heated at 80° C. in a sealed tube for 3 h. The mixture wascooled to rt and partitioned between EA (20 mL) and H₂O (20 mL). Theaqueous layer was extracted with EA (20 mL) and the combined organiclayers were dried over Na₂SO₄. The solvent was removed under reducedpressure and the crude product was purified by column chromatography onsilica gel elute with PE to give2-chloro-1-fluoro-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene (240 mg,62.3% yield) as colorless oil.

Step 2: Preparation of5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo-1-3yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution of(Z)—N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (239 mg, 10 mmol) and2-chloro-1-fluoro-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene (240 mg, 1.07mmol) in DMF (5 mL) at rt was added TEA (108 mg, 1.07 mmol). Thereaction mixture was stirred at rt for 18 h, poured into ice-water andextracted with EA (20 mL). The organic layer was washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography over silica gel elutedwith PE:EA (6:1) to give the final title compound5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol(140 mg; yield 30.6%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ9.21 (s, 1H), 7.80-7.70 (m, 4H), 7.64-7.60 (m, 2H), 4.43 (d, J=18.4 Hz,1H), 4.27 (d, J=18.4 Hz, 1H), 1.48 (s, 6H) ppm; HPLC purity: 96.0% at220 nm and 96.4% at 254 nm; MS: m/z=428.1 (M+, ESI+).

20.5-(5-(Fluoromethyl)-5-(3,4,5-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of 1,2,3-trichloro-5-(3-fluoroprop-1-en-2-yl)benzene

To a mixture of 1,2,3-trichloro-5-(prop-1-en-2-yl)benzene (660 mg, 3mmol) and1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diiumbis(tetrafluoroborate) (1.115 g, 3.15 mmol) in DMF (25 ml). The mixturewas stirred at 75° C. for 3 h. The mixture was washed with H₂O andextracted with EA (30 ml×2). The mixture was concentrated under reducedpressure. The residue was purified by column chromatography over silicagel eluted with PE:EA (7:1 to 5:1) to give the desired product (260 mg,yield 36%).

Step 2: Preparation of5-(5-(fluoromethyl)-5-(3,4,5-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution of(E)-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehydeoxime (225.5 mg, 1.1 mmol) in DMF (10 mL) at rt was added NCS (177 mg,1.32 mmol). The reaction mixture was warmed to 45° C., stirred for 2.5 hand cooled to rt. To a solution of1,2,3-trichloro-5-(3-fluoroprop-1-en-2-yl)benzene (260 mg, 1.1 mmol) andTEA (122.2 mg, 1.21 mmol) in DMF (20 mL) was added the above mixturedropwise at 0° C. The mixture was stirred at this temperature for 1 hand then at rt overnight. The mixture was acidified with HCl (3 N) to pHof 2 and then poured into water followed by extraction with EA (100ml×2). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-TLC eluted with PE:EA (2:1) to give the final titlecompound (200 mg, yield 41%) as a white solid: ¹H NMR (300 MHz,DMSO-d₆): δ 9.14 (s, 1H), 7.77 (s, 2H), 7.69-7.68 (m, 3H), 4.91 (s, 1H),4.75 (s, 1H), 3.80 (s, 2H), 1.45 (s, 6H). MS: m/z=443[M+H]+.

21.5-(5-(4-Bromo-3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of2-(4-bromo-3,5-dichlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

4,4,4′,4′,5,5,5′,5′-Octamethyl[2,2′-bi-1,3,2-dioxaborolane] (4.88 g,19.2 mmol), 2,6-bis(1-methylethyl)-N-(2-pyridinylmethylene)benzenamine(0.195 g, 0.73 mmol), and bis(1,5-cyclooctadiene)diiridium(I) dichloride(0.32 g, 0.48 mmol) were added to a solution of1,3-dichloro-2-bromobenzene (6.6 g, 29.5 mmol) in heptane (10 mL). Thereaction mixture color changed from yellow to forest green to brick redwithin the first minute. The reaction mixture was refluxed for 18 h. Themixture was then partitioned between EA and water, and the aqueousextract was washed twice with EA. The organic extracts were combined,dried over Na₂SO₄, and concentrated under reduced pressure. The solidresidue was purified by column chromatography over silica gel elutedwith PE-EA (8:1) to give2-(3,5-dichloro-4-(bromo)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(7 g, yield 68%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.75 (s,2H), 1.34 (s, 12H) ppm.

Step 2: Preparation of2-bromo-1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene

A mixture of2-(3,5-dichloro-4-(bromo)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1 g, 2.86 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (0.60 g, 3.43 mmol),Cs₂CO₃ (2.86 mL, 2M, 5.72 mmol) and Pd(PPh₃)₂Cl₂ (60 mg) in THF (30 mL)was heated at 70° C. in a sealed tube for 4 h. The mixture was cooled tort and partitioned between ether and H₂O. The aqueous layer wasextracted with EA and the combined organic layers were dried overNa₂SO₄. The solvent was removed under reduced pressure and the crudeproduct was purified by column chromatography over silica gel elutedwith hexanes to give1,3-dichloro-2-(trifluoromethyl)-5-(3,3,3-trifluoro-prop-1-en-2-yl)benzene(0.6 g; yield 66.7%) as colorless oil. ¹H NMR (400 MHz, DMSO-d₆): δ 7.72(s, 2H), 6.38 (s, 1H), 6.28 (s, 1H) ppm.

Step 3: Preparation of5-(5-(4-bromo-3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution ofN,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (0.25 g, 1.04 mmol) and1,3-dichloro-2-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene(400 mg, 1.26 mmol) in DMF (10 mL) at rt was added TEA (0.43 mL, 3.12mmol). The reaction mixture was stirred for 12 h, poured into ice-waterand extracted with EA. The organic layer was washed with brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by prep-TLC eluted with PE-EA (3:2) and thenpurified by prep-TLC to give the title compound (126 mg, yield 19.2%) asa white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.29 (s, 1H), 7.80-7.69 (m,5H), 4.45 (d, J=18.4 Hz, 1H), 4.35 (d, J=18.4 Hz, 1H), 1.48 (s, 3H),1.47 (s, 3H) ppm; HPLC purity: 95.4% at 214 nm and 98.7% at 254 nm MS:m/z=582 (M−1, ESI−).

22.5-(5-(3,5-Dichloro-4-methoxyphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of 4-bromo-2,6-dichlorophenol

A stirred solution of 2,6-dichlorophenol (20 g, 123.4 mmol) inacetonitrile (200 mL) was cooled to 0° C. and bromine (23.7 g) inacetonitrile (50 mL) was added dropwise. The red solution was stirred at0° C. for 2 h and a saturated aqueous solution of sodium sulphite wasadded until the red color disappeared. The phases were separated and theaqueous phase was extracted three times with ethyl acetate.Concentration of the combined organic phases gave a yellow oil, whichwas purified on a silica gel column (heptane/ethyl acetate, 10:1) togive 17.8 g of 4-bromo-2,6-dichlorophenol as a white solid. Yield: 60%;¹H NMR (400 MHz, CDCl₃): δ 7.42 (s, 2H), 5.9 (br s, 1H) ppm.

Step 2: Preparation of 5-bromo-1,3-dichloro-2-methoxybenzene

A mixture of 4-bromo-2,6-dichlorophenol (10 g, 41.67 mmol), K₂CO₃ (11.5g, 83.3 mmol) and CH₃I (8.88 g, 62.5 mmol) in DMF (100 mL) was stirredat rt for 16 h. TLC (EtOAc/petroleum ether=1:2) indicated completeconsumption of 4-bromo-2,6-dichlorophenol. The reaction mixture waspoured into water (300 mL). The aqueous phase was extracted with EtOAc(2×100 mL). The combined organic phases were dried over anhydrousNa₂SO₄, and concentrated in vacuuo to give crude5-bromo-1,3-dichloro-2-methoxybenzene, which was purified by columnchromatography (silica gel, EtOAc/petroleum ether=1:5) to yield theether product (9 g, yield 84.9%) as a white solid. ¹H NMR (400 MHz,CDCl₃): δ 7.45 (s, H), 3.91 (s, 3H) ppm.

Step 3: Preparation of2-(3,5-dichloro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 5-bromo-1,3-dichloro-2-methoxybenzene (1 g, 3.94 mmol),bis(pinacolato)diboron (1.46 g, 5.83 mmol), Pd(dppf)Cl₂ (0.135 g, 0.19mmol), KOAc (1.13 g, 11.6 mmol) in 1,4-dioxane (20 mL) was degassed withN₂ for 5 min. The reaction mixture was stirred at 70° C. for 16 h. TLC(EtOAc/Petroleum ether=1:5) indicated complete consumption of the bromostarting material. The reaction mixture was poured into water (40 mL)and extracted with EtOAc (3×70 mL). The combined organic phases weredried over anhydrous Na₂SO₄, and concentrated in vacuo to give crudeproduct, which was purified by column chromatography (silica gel,EtOAc/petroleum ether=1:10) to get the pure boron compound (0.5 g, yield42.4%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 7.71 (s, 2H), 3.91(s, 3H), 1.33 (s, 12H) ppm.

Step 4: Preparation of1,3-dichloro-2-methoxy-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene

A mixture of2-(3,5-dichloro-4-(methoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.4 g, 1.33 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (0.28 g, 1.59mmol), Cs₂CO₃ (1.33 mL, 2M, 2.66 mmol) and Pd(PPh₃)₂Cl₂ (28 mg) in THF(30 mL) was heated at 70° C. in a sealed tube for 4 h. The mixture wascooled to rt and partitioned between ether and H₂O. The aqueous layerwas extracted with EA and the combined organic layers were dried overNa₂SO₄. The solvent was removed under reduced pressure and the crudeproduct was purified by column chromatography over silica gel elutedwith hexanes to give1,3-dichloro-2-(trifluoromethyl)-5-(3,3,3-trifluoro-prop-1-en-2-yl)benzene(0.2 g, yield 56%) as colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 7.39 (s,2H), 6.00 (s, 1H), 5.78 (s, 1H), 3.93 (s, 3H) ppm.

Step 5: Preparation of5-(5-(3,5-dichloro-4-methoxyphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution of crude compoundN,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxa-borole-5-carbimidoylchloride (0.29 g, 1.23 mmol) and1,3-dichloro-2-methoxy-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (0.4 g,1.48 mmol) in DMF (10 mL) at rt was added TEA (0.51 mL, 3.67 mmol). Thereaction mixture was stirred for 12 h, poured into ice-water andextracted with EA. The organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-TLC eluted with PE-EA (3:2) and then purified bypreparative TLC to give the title compound (110 mg, yield 15.6%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.27 (s, 1H), 7.82-7.75 (m,5H), 4.46 (d, J=18.4 Hz, 1H), 4.36 (d, J=18.4 Hz, 1H), 3.93 (s, 3H),1.53 (s, 6H) ppm; MS: m/z=472 (M−1, ESI−).

23.5-(5-(3,4-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of1,2-dichloro-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene

A mixture of (3,4-dichlorophenyl)boronic acid (500 mg, 2.62 mmol),2-bromo-3,3,3-trifluoroprop-1-ene (501 mg, 2.88 mmol), K₂CO₃ (723 mg,5.24 mmol) and Pd(PPh₃)₂Cl₂ (36 mg, 0.052 mmol) in THF (2 mL) and H₂O (1mL) was heated at 80° C. in a sealed tube for 3 hours. The mixture wascooled to rt and partitioned between EA (20 mL) and H₂O (20 mL). Theaqueous layer was extracted with EA (20 mL) and the combined organiclayers were dried over Na₂SO₄. The solvent was removed under reducedpressure and the crude product was purified by column chromato-graphyover silica gel eluted with PE to give1,2-dichloro-4-(3,3,3-trifluoroprop-1-en-2-yl)-benzene (400 mg, 63.3%yield) as colorless oil.

Step 2: Preparation of5-(5-(3,4-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution of(Z)—N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (397 mg, 1.66 mmol) and1,2-dichloro-4-(3,3,3-trifluoroprop-1-en-2-yl) benzene (400 mg, 1.66mmol) in DMF (5 mL) at rt was added TEA (168 mg, 1.66 mmol). Thereaction mixture was stirred at rt for 18 h, poured into ice-water andextracted with EA (20 mL). The organic layer was washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography over silica gel elutedwith PE:EA (6:1) to give the final title compound5-(5-(3,4-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol(180 mg; yield 24.4%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ9.20 (s, 1H), 7.83-7.60 (m, 5H), 4.45 (d, J=18.8 Hz, 1H), 4.26 (d,J=18.4 Hz, 1H), 1.48 (s, 6H) ppm; HPLC purity: 96.8% at 220 nm and 97.5%at 254 nm; MS: m/z=444.3 (M+, ESI+).

24.5-(5-(4-Fluoro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of2-(4-fluoro-3-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane

The mixture of 4-fluoro-3-(trifluoromethyl)phenylboronic acid (2.08 g,10 mmol) and ethane-1,2-diol (3.72 g, 60 mmol) in toluene (150 ml) wasrefluxed with a Dean-stark trap for 2 h, then cooled to rt. The solventwas concentrated to dryness to afford the crude product (2.7 g, 100%).¹H NMR (300 MHz, CDCl₃): δ 8.08-8.05 (d, 1H), 8.01-7.96 (t, 1H),7.24-7.17 (t, 1H), 4.40 (s, 4H) ppm.

Step 2: Preparation of1-fluoro-2-(trifluoromethyl)-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene

The mixture of2-(4-fluoro-3-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (2.34 g, 10mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (2.10 g, 12 mmol), Pd(Ph₃P)₂Cl₂(0.281 g, 0.4 mmol) and K₂CO₃ (2.76 g, 20 mmol) in THF (30 mL) and H₂O(15 mL) was heated at 70° C. overnight. Then the reaction mixture wascooled down to rt, added water and extracted with ethyl acetate, washedwith brine, dried with Na₂SO₄, concentrated to dryness to afford thecrude product. It was further purified by column chromatography elutedwith PE to afford the desired product (0.6 g, yield 23.3%) as lightyellow oil. ¹H NMR (300 MHz, CDCl₃): δ 7.69-7.62 (m, 2H), 7.27-7.21 (t,1H), 6.05 (d, 1H), 5.80 (d, 1H) ppm.

Step 3: Preparation of5-(5-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution of(Z)—N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (522 mg, 2.18 mmol) in DMF (5 mL) was successively added1-fluoro-2-(trifluoromethyl)-4-(3,3,3-trifluoroprop-1-en-2-yl)benzene(563 mg, 2.18 mmol) and TEA (440 mg, 4.36 mmol) below −10° C. Themixture was stirred at rt overnight, poured into 1N HCl solution andextracted with EA (30 mL×3). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by pre-TLC eluted with PE:EA (1:1, 1%HOAc) and pre-HPLC to give the final title compound (200 mg, yield20.0%) as white solid: ¹H NMR (300 MHz, DMSO-d₆): δ 9.20 (s, 1H),8.03-8.00 (m, 1H), 7.91-7.89 (d, J=12 Hz, 1H), 7.77-7.68 (m, 4H),4.52-4.46 (d, J=18 Hz, 1H), 4.36-4.30 (d, J=18 Hz, 1H), 1.48 (s, 6H).LC-MS: 462 [M+H]+.

25.5-(5-(3-Chloro-4,5-difluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of 3-chloro-4,5-difluoroaniline

1-Chloro-2,3-difluoro-5-nitrobenzene (3 g, 15.6 mmol) was added toacetic acid (10 mL) and methanol (250 mL). To this mixture was addediron powder (3.0 g) in portions, stirred for 2 h at 60-65° C., cooled toroom temperature, and filtered. The filterate was stripped to a brownsolid, which was extracted with ethyl acetate (3×200 mL), washed with 1NNaOH (3×100 mL), and brine (2×100 mL). The organic layer was dried overanhydrous magnesium sulfate, filtered and stripped down to yield theproduct as a pale yellow solid (2.6 g). Yield 100%; ¹H NMR (400 MHz,CDCl₃): δ 6.41 (m, 2H), 3.65 (br s, 2H) ppm.

Step 2: Preparation of 5-bromo-1-chloro-2,3-difluorobenzene

To a solution of 3-chloro-4,5-difluoroaniline (2.1 g, 12.96 mmol) inhydrobromic acid (40% in H₂O, 18.7 mL) was added dropwise a solution ofsodium nitrite (0.96 g, 13.6 mol) in 7.5 mL H₂O at 0° C. Then themixture was poured into a solution of copper(I) bromide (3.5 g, 23.7mmol) in hydrobromic acid (40% in H₂O, 15 mL) at 0° C. The cooling bathwas then removed and the mixture was heated at 60° C. overnight. Aftercooling, the mixture was basified with a solution 2N NaOH solution topH=9 and diluted with CH₂Cl₂. After separation, the combined organiclayers were washed with brine, dried over Na₂SO₄ and then concentratedto get crude product, which was purified by column with PE/EtOAc (from100:1 to 20:1) as eluant to afford 2 g product. Yield 68.3%; ¹H NMR (400MHz, CDCl₃): δ 7.37-7.35 (m, 1H), 7.30-7.25 (m, 1H) ppm.

Step 3: Preparation of2-(3-chloro-4,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 5-bromo-1-chloro-2,3-difluorobenzene (2 g, 8.85 mmol),bis(pinacolato)diboron (3.30 g, 13.1 mmol), Pd(dppf)Cl₂ (0.30 g, 0.43mmol), KOAc (2.54 g, 26.1 mmol) in 1,4-dioxane (20 mL) was degassed withN₂ for 5 min. The reaction mixture was stirred at 70° C. for 16 h. TLC(EtOAc/Petroleum ether=1:5) indicated complete consumption of the bromocompound. The reaction mixture was poured into water (40 mL) andextracted with EtOAc (3×70 mL). The combined organic phases were driedover anhydrous Na₂SO₄, and concentrated in vacuo to give the residue,which was purified by column chromatography (silica gel, EtOAc/petroleumether=1:10) to get the product (1.3 g, yield 54.2%) as a white solid. ¹HNMR (400 MHz, CDCl₃): δ 7.61-7.55 (m, 1H), 7.51-7.46 (m, 1H), 1.38 (s,12H) ppm.

Steps 4 and 5: Preparation of5-(5-(3-chloro-4,5-difluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

A mixture of2-(3-chloro-4,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.2 g, 4.38 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (920 mg, 5.26mmol, 1.2 eq), Na₂CO₃ (1.39 g, 13.14 mmol, 3 eq) and Pd(dppf)Cl₂ (358mg, 10% mol) in DME (50 mL) and water (2 mL) was heated at 70 to 80° C.for 2 h. The mixture was cooled to 0° C. with ice-water bath, and thenused to next step without work-up. To the reaction mixture were addedTEA (1.33 g, 1.83 mL, 13.14 mmol, 3 eq) andN,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (841 mg, 3.50 mmol, 0.8 eq) at 0° C. The reaction mixture wasstirred for 12 h at rt, poured into ice-water and extracted with EA. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica gel column and prep-HPLC to give 125 mg final titleproduct. ¹H NMR (400 MHz, DMSO-d₆): δ 9.22 (s, 1H), 7.76-7.66 (m, 5H),4.43 (d, J=18.4 Hz, 1H), 4.31 (d, J=18.4 Hz, 1H), 1.48 (s, 6H) ppm; MS:m/z=444/504 (M−1, ESI−).

26.5-(5-(3,4-Dichloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of2-(3,4-dichloro-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 5-bromo-1,2-dichloro-3-fluorobenzene (2 g, 8.3 mmol),bis(pinacolato)diboron (3.1 g, 12.4 mmol), Pd(dppf)Cl₂ (0.33 g, 0.41mmol), KOAc (2.4 g, 24.7 mmol) in 1,4-dioxane (50 mL) was degassed withN₂ for 5 minutes. The reaction mixture was stirred at 70° C. for 16 h.TLC (EtOAc/Petroleum ether=1:5) indicated complete consumption of thebromo starting material. The reaction mixture was poured into water (40mL) and extracted with EtOAc (3×70 mL). The combined organic phases weredried over anhydrous Na₂SO₄, and concentrated in vacuo to give a cruderesidue, which was purified by column chromatography (silica gel,EtOAc/petroleum ether=1:10) to give the boron intermediate (2.0 g,yield: 83.3%) as a white solid.

Steps 2 and 3: Preparation of5-(5-(3,4-dichloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

A mixture of2-(3,4-dichloro-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.5 g, 1.73 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (0.38 g, 2.16mmol), Cs₂CO₃ (1.8 mL, 2M, 3.6 mmol) and Pd(PPh₃)₂Cl₂ (38 mg) in THF (10mL) was heated at 70° C. in a sealed tube for 4 h. The mixture wascooled to rt, and thenN,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (345 mg, 1.44 mmol) in DMF (20 mL) at rt and TEA (0.6 mL, 4.32mmol) were added. The reaction mixture was stirred for 12 h, poured intoice-water and extracted with EA. The organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column eluted with PE-EA (10:1 to3:1) and then purified by prep-TLC to give 80 mg of the title compoundas a white solid (yield 10%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.23 (s, 1H),7.77-7.69 (m, 5H), 4.44 (d, J=18.8 Hz, 1H), 4.32 (d, J=18.8 Hz, 1H),1.47 (s, 6H) ppm; MS: m/z=462 (M+1, ESI+).

27.5-(5-(3,5-Dibromo-4-chlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

Step 1: 1,3-dibromo-2-chlorobenzene

To a mixture of isoamyl nitrite (585 mg, 5 mmol) and CuCl (396 mg, 4mmol) in acetonitrile (10 mL) was slowly added 2,6-dibromoaniline (502mg, 2 mmol) at 65° C. The reaction mixture was stirred at 65° C. for 2h. and then NH₄BF₄ solution (4.2 g, 40 mmol) was added dropwise. Thereaction mixture was stirred at 0-10° C. for 1 h, cooled to rt,concentrated under reduced pressure, dissolved with EA (30 mL), washedwith water (20 mL). The organic layer was dried over Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography eluted with PE to give 1,3-dibromo-2-chlorobenzene(270 mg, yield 49%) as solid.

Step 2:2-(3,5-dibromo-4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(3)

To a solution of 1,3-dibromo-2-chlorobenzene (270 mg, 1 mmol) inn-heptane (15 mL) was added Pin₂B₂ (170 mg, 0.67 mmol),cycloocta-1,5-diene iridium salt (11 mg, 0.017 mmol) and2,6-diisopropyl-N-(pyridin-2-ylmethylene)aniline (7 mg, 0.025 mmol). Themixture was refluxed for 4 h under N₂, cooled to rt, quenched withwater, extracted with EA (3×50 mL). The combined organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatographyeluted with PE:EA=80:1 to give2-(3,5-dibromo-4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(265 mg, yield 67%) as solid.

Step 3: 1,3-dibromo-2-chloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene

A mixture of2-(3,5-dibromo-4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(260 mg, 0.66 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (172 mg, 0.98mmol), Pd(dppf)Cl₂ (91 mg, 0.13 mmol), K₂CO₃ (182 mg, 1.32 mmol) in THF(2 mL) and water (0.5 mL) was heated at 80° C. in a sealed vial under N₂atmosphere for 12 h, cooled to rt, quenched with water, extracted withEA (3×10 mL). The combined organic layer was washed with brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography eluted with PE to give1,3-dibromo-2-chloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (135 mg,yield 56%) as oil.

Step 4:5-(5-(3,5-dibromo-4-chlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution ofN,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride(68 mg, 0.28 mmol) in DMF was added1,3-dibromo-2-chloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (132 mg,0.36 mmol) and TEA (31 mg, 0.36 mmol) at rt. The mixture was stirred at25° C. for 12 h, quenched with water, extracted with EA (3×10 mL). Thecombined organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography eluted with PE:EA=5:1 to give thefinal title compound5-(5-(3,5-dibromo-4-chlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol(38 mg; yield 22%) as solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.21 (s, 1H),7.96 (s, 2H), 7.76-7.69 (m, 3H), 4.45-4.30 (q, 2H), 1.48 (s, 6H) ppm;MS: m/z=568 (M+1, ESI+).

28.(S)-5-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

The title compound was obtained by separation of the racemic mixture of5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-olwith chiral column chromatography. The racemic mixture was dissolved inthe solvent of mobile phase and separated by supercritical fluid (SFC)chiral chromatography. The chromatography conditions used were: columnCHIRALCEL OJ-H (column size: 0.46 cm I.D.×15 cm length), mobile phaseCO₂/MeOH=70/30 (w/w), flow rate 2.0 mL/min, detector wave length UV 220nm, and temperature 35° C.

29.(R)-5-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

The title compound was obtained by separation of the racemic mixture of5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-olwith chiral column chromatography. The racemic mixture was dissolved inthe solvent of mobile phase and separated by supercritical fluid (SFC)chiral chromatography. The chromatography conditions used were: columnCHIRALCEL OJ-H (column size: 0.46 cm I.D.×15 cm length), mobile phaseCO₂/MeOH=70/30 (w/w), flow rate 2.0 mL/min, detector wave length UV 220nm, and temperature 35° C.

30.5-(5-(4-Chloro-3,5-difluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

The title compound was synthesized by the following scheme:

To a solution of(E)-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehydeoxime (200 mg, 0.98 mmol) in DMF (7 mL) at rt was added NCS (157 mg,1.17 mmol). The reaction mixture was warmed to 45° C., stirred for 2.5 hand cooled to rt. This mixture was added dropwise to a solution of2-chloro-1,3-difluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (237 mg,0.98 mmol) and TEA (218 mg, 2.16 mmol) in DMF (7 mL) at 0° C. Themixture was stirred at this temperature for 1 h, and then at rtovernight. The mixture was acidified with 3 N HCl to pH of 2, thenpoured into water and extracted with EA (50 mL×2). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-TLC (PE:EA=2:1) to give the final title compound (150 mg, yield35%) as white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.24 (s, 1H),7.82-7.73 (m, 3H), 7.71-7.60 (m, 2H), 4.50 (d, J=18.3 Hz, 1H), 4.44 (d,J=18.3 Hz, 1H), 1.51 (s, 3H), 1.50 (s, 3H) ppm; HPLC purity: 95.5% at214 nm and 97.8% at 254 nm; MS: m/z=446 (M+1, ESI+).

31.3,3-Dimethyl-5-(5-(trifluoromethyl)-5-(3,4,5-trifluorophenyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of1,2,3-trifluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene

A mixture of (3,4,5-trifluorophenyl)boronic acid (0.5 g, 2.84 mmol),2-bromo-3,3,3-trifluoroprop-1-ene (596 mg, 3.41 mmol, 1.2 eq), Na₂CO₃(0.90 g, 8.52 mmol, 3 eq) and Pd(dppf)Cl₂ (232 mg, 10% mol) in DME (20mL) and water (2 mL) was heated at 70 to 80° C. for 2 h. The mixture wascooled to 0° C. with ice-water bath, and then used to next step withoutfurther purification.

Step 2: Preparation of3,3-dimethyl-5-(5-(trifluoromethyl)-5-(3,4,5-trifluorophenyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol

To a solution of1,2,3-trifluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene in DMF wereadded TEA (0.86 g, 1.18 mL, 8.52 mmol, 3 eq) andN,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (545 mg, 2.27 mmol, 0.8 eq) at 0° C. The reaction mixture wasstirred for 12 h at rt, poured into ice-water and extracted with EA. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by silica column and prep-HPLC to give 105 mg pure product. ¹HNMR (400 MHz, DMSO-d₆): δ 9.23 (s, 1H), 7.76-7.59 (m, 5H), 4.43 (d,J=18.4 Hz, 1H), 4.28 (d, J=18.4 Hz, 1H), 1.48 (s, 3H), 1.47 (s, 3H) ppm;HPLC purity: 99.6% at 254 nm; MS: m/z=430 (M+1, ESI+).

32.5-(5-(3,5-Dibromo-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

Step 1: 1,3-dibromo-2-fluorobenzene

To a mixture of 2,6-dibromoaniline (5.0 g, 20 mmol) and HCl (12 N, 10mL) was added NaNO₂ (2.1 g, 30 mmol) at 0° C. The reaction mixture wasstirred at 0-10° C. for 1 h, and then NH₄BF₄ solution (4.2 g, 40 mmol)was added dropwise. The reaction mixture was stirred at 0-10° C. for 1h. The precipitate was filtered and dried. The residue obtained washeated to 220° C. for 2 h, cooled to rt and dissolved with EA (150 mL),washed with NaOH (2 N, 200 mL). The organic layer was dried over Na₂SO₄,filtered and concentrated under reduced pressure to give1,3-dibromo-2-fluorobenzene (1.45 g, yield 29%).

Step 2:2-(3,5-dibromo-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a solution of 1,3-dibromo-2-fluorobenzene (1.43 g, 5.63 mmol) inn-heptane (100 mL) was added Pin₂B₂ (953 mg, 3.75 mmol),cycloocta-1,5-diene iridium salt (63 mg, 0.094 mmol) and2,6-diisopropyl-N-(pyridin-2-ylmethylene)aniline (37 mg, 0.14 mmol). Themixture was refluxed for 4 h under N₂, cooled to rt, quenched withwater, extracted with EA (3×50 mL). The combined organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatographyeluted with PE:EA=80:1 to give2-(3,5-dibromo-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.046 g, yield 49%) as solid.

Step 3: 1,3-dibromo-2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene

A mixture of2-(3,5-dibromo-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(300 mg, 0.79 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (207 mg, 1.18mmol), Pd(dppf)Cl₂ (112 mg, 0.16 mmol), K₂CO₃ (218 mg, 1.58 mmol) inTHF(2 mL) and water (1 mL) was heated at 80° C. in a sealed vial underN₂ atmosphere for 12 h, cooled to rt, quenched with water, extractedwith EA (3×10 mL). The combined organic layer was washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography eluted with PE to give1,3-dibromo-2-fluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (100 mg,yield 30%) as solid.

Step 4:5-(5-(3,5-dibromo-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution ofN,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (34 mg, 0.14 mmol) in DMF (3 mL) was added1,3-dibromo-2-fluoro-5-(3,3,3-trifluoro-prop-1-en-2-yl)benzene (50 mg,0.14 mmol) and TEA (15 mg, 0.14 mmol) at rt. The mixture was stirred at25° C. for 12 h, quenched with water, extracted with EA (3×10 mL). Thecombined organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by columnchromatography eluted with PE:EA(5:1) to give the final title compound5-(5-(3,5-dibromo-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol(50 mg; yield 59%) as solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.22 (s, 1H),7.92-7.68 (m, 5H), 4.45-4.40 (q, J=22 Hz, 1H), 4.34-4.30 (q, J=22 Hz,1H), 1.48 (s, 6H) ppm; HPLC purity: 96.9% at 220 nm and 98.4% at 254 nm;MS: m/z=552.0 (M+1, ESI+).

33.3,3-Bis(fluoromethyl)-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-adihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of 2-iodo-4-methylaniline

To a solution of 4-methylaniline (53.5 g, 500 mmol) in DCM (200 mL) wasadded a solution of NaHCO₃ (50.4 g) in water (500 mL), and then I₂(127g) was added. The mixture was stirred at rt overnight. The mixture wastreated with aqueous NaHSO₃ and extracted with DCM. The combined organiclayers were washed with brine, dried over Na₂SO₄, and then concentratedin vacuo to afford the product as brown oil (110 g, yield 95%). ¹H NMR(300 MHz, CDCl₃): δ 7.48 (dd, J=1.8 & 0.6 Hz, 1H), 6.96 (dd, J=8.1 & 1.8Hz, 1H), 6.67 (d, J=8.1 Hz, 1H), 3.98 (bs, 2H), 2.22 (s, 3H) ppm.

Step 2: Preparation of 1-bromo-2-iodo-4-methylbenzene

To a mixture of 2-iodo-4-methylaniline (50 g, 214.55 mmol) in HOAc (250mL), H₂SO₄ (10 mL), and H₂O (40 mL) was added a solution of NaNO₂ (14.5g) in H₂O (80 mL) at 0° C. The solution was stirred for 1.5 h. This wasdefined as mixture A. In another round bottom flask, a mixture of NaBr(107 g), CuSO₄ (32.2 g), Cu (38.9 g), H₂SO₄ (39 mL), and H₂O (25 mL) wasrefluxed for 1.5 h. To this mixture was added mixture A, and thesolution was then refluxed for 3 h. The solution was treated with waterand extracted with EA (500 mL×3). The combined organic layers werewashed with brine, dried over Na2SO4, and then concentrated in vacuo.Purification by column chromatography over silica gel eluted with PEafforded the product as colorless oil (43 g, yield 68%). ¹H NMR (300MHz, CDCl₃): δ 7.69 (m, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.00 (m, 1H), 2.26(s, 3H) ppm.

Step 3: Preparation of2-(2-bromo-5-methylphenyl)-1,3-difluoropropan-2-ol

To a solution of 1-bromo-2-iodo-4-methylbenzene (18.5 g, 62.3 mmol) inTHF (50 mL) at 0° C. was slowly added i-PrMgCl (12 mL, 23.47 mmol).After stirring for 1 h at 0° C., the reaction temperature was cooled to−70° C. Then a solution of 1,3-difluoropropan-2-one (1.7 g, 18.05 mmol)in dry THF (5 mL) was added. The mixture was stirred at −70° C. for 1 h,and then dry ice bath was removed. The solution was acidified with 2 NHCl and extracted with EA (60 mL×2). The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatography oversilica gel eluted with PE:EA (25:1) to give the desired product (2.5 g,yield 53%) as colorless oil. ¹H NMR (300 MHz, CDCl₃): δ 7.61 (d, J=1.8Hz, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.02-6.99 (m, 1H), 5.13-5.09 (m, 1H),5.02-4.94 (m, 2H), 4.87-4.82 (m, 1H), 3.27 (bs, 1H), 2.33 (s, 3H) ppm.

Step 4: Preparation of1-bromo-2-(2-(ethoxymethoxy)-1,3-difluoropropan-2-yl)-4-methylbenzene

NaH (362 mg, 9.05 mmol) was added to a solution of2-(2-bromo-5-methylphenyl)-1,3-difluoropropan-2-ol (2.0 g, 7.54 mmol) inTHF (10 mL) slowly at 0° C. MEMCl (1.41 g, 11.32 mmol) was addeddropwise. The mixture was stirred at rt overnight. The mixture wasdiluted with H₂O and extracted with EA (50 mL×2). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography over silica gel eluted with PE:EA (10:1 to 6:1) to givethe product (1.8 g, yield 68%) as colorless oil.

Step 5: Preparation of3,3-bis(fluoromethyl)-5-methylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution of1-bromo-2-(2-(ethoxymethoxy)-1,3-difluoropropan-2-yl)-4-methylbenzene(1.8 g, 5.10 mmol) in THF (15 mL) at −78° C. was slowly added n-BuLi(5.1 mL, 12.75 mmol). After stirring for 10 min, a solution of B(OMe)₃(1.06 g, 10.2 mmol) in dry THF (5 mL) was added dropwise. The mixturewas stirred at −78° C. for 0.5 h, and then dry ice bath was removed. Thesolution was acidified with HCl (4 N) and extracted with EA (100 mL×2).The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography over silica gel eluted with PE:EA (5:1to 3:1) to give the desired compound (350 mg, yield 32%) as white solid.

Step 6: Preparation of3,3-bis(fluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde

A solution of3,3-bis(fluoromethyl)-5-methylbenzo[c][1,2]oxaborol-1(3H)-ol (350 mg,1.65 mmol), NBS (647 mg, 3.63 mmol), and BPO (40 mg, 0.17 mmol) in CCl₄(10 mL) was refluxed overnight. After treating with aqueous Na₂CO₃, theaqueous phase was acidified with HCl (3 N) to pH of 3, and thenextracted with EA. The organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure to afford thecrude product (400 mg) as a yellow solid that was used directly in thenext step without purification. ¹H NMR (300 MHz, CDCl₃): δ 10.09 (s,1H), 7.98-7.94 (m, 3H), 4.79-4.74 (m, 2H), 4.63-4.59 (m, 2H).

Step 7: Preparation of(E)-3,3-bis(fluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehydeoxime

To a mixture of3,3-bis(fluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde(400 mg, 1.77 mmol) and NH₂OH.HCl (148 mg, 2.12 mmol) in THF (25 mL) andH₂O (5 mL) at rt was added NaOAc (203 mg, 2.48 mmol). The mixture wasstirred at rt overnight, diluted with H₂O and extracted with EA (50mL×2). The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The crudeproduct (440 mg) was used directly in the next step withoutpurification.

Step 8: Preparation of3,3-bis(fluoromethyl)-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol

To a solution of(E)-3,3-bis(fluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehydeoxime (440 mg, 1.83 mmol) in DMF (10 mL) at rt was added NCS (294 mg,2.19 mmol). The reaction mixture was warmed to 45° C., stirred for 2.5 hand cooled to rt. To a solution of1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (577 mg, 2.10mmol) and TEA (403 mg, 4.0 mmol) in DMF (10 mL) was added the abovemixture dropwise at 0° C. The mixture was stirred at 0° C. for 1 h, thenstirred at rt overnight. The mixture was acidified with HCl (3 N) to pHof 2, then poured into water and extracted with EA (50 mL×2). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by prep-TLC (PE:EA=2:1) to give the final title compound (150mg, 16%) as white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.74 (s, 1H),7.96-7.80 (m, 5H), 4.89-4.80 (m, 2H), 4.73-4.64 (m, 2H), 4.46 (d, J=17.4Hz, 1H), 4.35 (d, J=17.4 Hz, 1H) ppm; HPLC purity: 95.3% at 214 nm; MS:m/z=516 (M+1, ESI+).

34.3,3-Dimethyl-5-(5-(2,3,4,5-tetrachlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol

To the solution ofN,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (0.526 mmol) in DMF (3 mL) was added1,2,3,4-tetrachloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (245 mg,0.789 mmol) and TEA (106 mg, 1.052 mmol) at rt. The mixture was stirredat 25° C. for 12 h, quenched with water, extracted with EA (3×10 mL).The combined organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by prep-HPLC to give the final title compound3,3-dimethyl-5-(5-(2,3,4,5-tetrachlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol(52 mg; yield 13%) as a solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.20 (s,1H), 7.98 (s, 1H), 7.83 (s, 1H), 7.76-7.47 (d, J=3.2 Hz, 2H), 4.67-4.63(d, J=18 Hz, 1H), 4.37-4.35 (d, J=18.8 Hz, 1H), 1.49 (s, 3H), 1.48 (s,3H) ppm; MS: m/z=514 (M+1, ESI+).

35.5-(5-(3,5-Dichloro-2,4-difluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of 1-bromo-3,5-dichloro-2,4-difluorobenzene

To a solution of 3,5-dichloro-2,4-difluorobenzenamine (9.9 g, 50.0 mmol)in HBr (200 mL) was added a solution of NaNO₂ (3.45 g, 50.0 mmol) in H₂O(80 mL) slowly under salt ice-bath, then the mixture was stirred for 2h, and CuBr (7.15 g, 50.0 mmol) was added at 0° C. The mixture wasstirred for additional 2 h, and then poured into water (100 mL),extracted with DCM, dried over NaSO₄, filtered and concentrated underreduced pressure. The resulting residue was purified by chromatographyover silica gel eluted with PE to give compound1-bromo-3,5-dichloro-2,4-difluorobenzene (6.2 g, yield 48%) as acolorless oil. ¹H NMR (400 MHz, CDCl₃): δ 7.49 (t, J=7.2 Hz, 1H) ppm.

Step 2: Preparation of2-(3,5-dichloro-2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 1-bromo-3,5-dichloro-2,4-difluorobenzene (6.2 g, 23.75mmol), bis(pinacolato)-diboron (18.1 g, 71.25 mmol), Pd(dppf)Cl₂ (521mg, 0.713 mmol) and KOAc (6.98 g, 71.25 mmol) in 1,4-dioxane (150 mL)was stirred at 80° C. overnight under argon. Water (200 mL) was addedand the mixture was extracted three times with ethyl acetate. Thecombined extracts were washed with water and brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography over silica gel eluted with PE-EA(10:1) to give2-(3,5-dichloro-2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneas a white solid.

Step 3: Preparation of1,3-dichloro-2,4-difluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)-benzene

A mixture of2-(3,5-dichloro-2,4-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(7.34 g, 23.75 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (5.82 g, 33.25mmol), Cs₂CO₃ (15.5 g, 47.5 mmol) and Pd(PPh₃)₂Cl₂ (400 mg) in THF (30mL) and water (15 mL) was heated at 70° C. in a sealed tube for 4 hunder argon. The mixture was cooled to rt and partitioned between EA andH₂O. The aqueous layer was extracted with EA and the combined organiclayers were dried over Na₂SO₄. The solvent was removed and the residuewas purified by column chromatography on silica gel eluted with hexanesto give crude compound of1,3-dichloro-2,4-difluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (3.93g) as a colorless oil. It was used in next step without furtherpurification.

Step 4: Preparation of5-(5-(3,5-dichloro-2,4-difluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution ofN,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]-oxaborole-5-carbimidoylchloride (3.0 g, 12.63 mmol) and1,3-dichloro-2,4-difluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)-benzene(3.93 g, 14.19 mmol) in DMF (20 mL) at rt was added TEA (2.7 mL, 18.95mmol). The reaction mixture was stirred for 12 h, poured into ice-waterand extracted with EA. The organic layer was washed with brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography over silica gel elutedwith PE-EA (1:1) to give the title compound5-(5-(3,5-dichloro-2,4-difluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol[1.3 g, yield: 21.4% (3 steps)] as a white solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.23 (s, 1H), 7.87 (t, J=7.5 Hz, 1H), 7.83 (s, 1H), 7.75 (s,2H), 4.59 (d, J=18.5 Hz, 1H), 4.37 (d, J=18.5 Hz, 1H), 1.50 (s, 3H),1.48 (s, 3H) ppm; HPLC purity: 100.0% at 220 nm and 100.0% at 254 nm;MS: m/z=479.8 (M+1, ESI+).

36.5-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-diethyl-benzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of 2-iodo-4-methylaniline

To a stirred solution of p-toluidine (50 g, 467 mmol) in methylenechloride (250 mL) was added a solution of sodium bicarbonate (47 g, 560mmol) in water (750 mL). Then it was added iodine (118.6 g, 467 mmol) insmall portions and the mixture was stirred for 16 h at room temperature.The reaction was quenched with saturated NaHSO₃ and the product wasextracted with methylene chloride. The methylene chloride layer waswashed with brine, dried over Na₂SO₄, and evaporated in vacuum to givethe crude product (100 g, yield 92%). ¹H NMR (300 MHz, CDCl₃): δ 7.46(s, 1H), 7.13-6.95 (d, 1H), 6.68-6.64 (d, 1H), 4.00 (br, 2H), 2.21 (s,3H). MS: m/z 234 [M+1]⁺.

Step 2: Preparation of 1-bromo-2-iodo-4-methylbenzene

2-Iodo-4-methylaniline (100 g, 450 mmol) was suspended in the mixture ofwater (200 mL) and HBr (48%, 300 mL). The mixture was refluxed for 15min. Then the mixture was cooled to 0° C., and NaNO₂ (31.05 g, 0.45 mol)in water (150 ml) was added dropwise at such a rate that the temperaturedid not exceed 5° C. The diazonium solution wad stirred for a further 30min at 0-5° C. and then added slowly to a stirred mixture of CuBr (64.5g, 0.45 mol) in HBr (48%, 250 mL) and water (250 ml) at roomtemperature. The mixture was poured into ice and extracted with CH₂Cl₂(500 ml×3). The methylene chloride layer was washed with brine, driedover Na₂SO₄, and evaporated in vacuum to give the crude product (109 g,yield 81.8%). It can be further purified by column chromatographyeluting with petroleum ether. MS: 297 [M+1]⁺.

Step 3: Preparation of 3-(2-bromo-5-methylphenyl)pentan-3-ol

To a solution of 1-bromo-2-iodo-4-methylbenzene (28 g, 94 mmol) in THF(10 ml) at −10° C. under nitrogen was slowly added i-PrMgBr (47 ml, 94mmol). The reaction mixture was stirred for 1 h at −10° C. Then thereaction mixture was cooled to −30° C., and pentan-3-one (8.1 g, 94mmol) was added dropwise. The reaction mixture was stirred for 1 h at−30° C. under nitrogen and then warmed to rt and stirred for additional2 h. Then the reaction mixture was quenched with 2N HCl solution andextracted with EA. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography over silica gel elutedwith PE:EA (10:0 to 5:1) to give the desired compound (6.5 g, yield26.9%) as colorless oil. ¹H NMR (300 MHz, CDCl₃): δ 7.52-7.50 (d, 1H),7.43-7.40 (d, 1H), 6.95-6.92 (d, 1H), 2.48-2.40 (q, 2H), 2.31 (s, 3H),1.86-1.78 (q, 2H), 0.77-0.71 (m, 6H). MS: m/z=257 and 259 [M+1]⁺.

Step 4: Preparation of3,3-diethyl-5-methylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution of 3-(2-bromo-5-methylphenyl)pentan-3-ol (6.5 g, 25.2mmol) in THF (150 ml) at −78° C. was slowly added n-BuLi (30.24 ml, 75.6mmol). The reaction mixture was warmed to rt and stirred for 2 h. Afterbeing cooled to −78° C., trimethyl borate (5.23 g, 50.4 mmol) was addeddropwise and the reaction mixture was warmed to rt, stirred for 10 hunder nitrogen and quenched with 2N HCl (50 ml). The mixture wasextracted with EA (40 ml×3). The combined organic layers were washedwith water and brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatography oversilica gel eluted with PE:EA (10:1 to 1:1) to give the product (2.0 g,yield 38.9%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 8.87 (s,1H), 7.52-7.47 (d, 1H), 7.11-7.06 (m, 2H), 2.35 (s, 3H), 1.88-1.68 (m,4H), 0.60-0.45 (m, 6H). MS: m/z=205 [M+1]⁺.

Step 5: Preparation of3,3-diethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde

To a solution of 3,3-diethyl-5-methylbenzo[c][1,2]oxaborol-1(3H)-ol (2.0g, 9.8 mmol) in CCl₄ (25 ml) at rt was added benzoyl peroxide (237 mg,0.98 mmol) followed by NBS (3.489 g, 19.6 mmol). The reaction mixturewas refluxed for 16 h, cooled to rt and treated with aqueous Na₂CO₃. Theaqueous layer was acidified with 3N HCl to pH=3 and extracted with EA(50 ml×3). The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the desiredproduct (1.2 g, yield 56%) as white solid. ¹H NMR (300 MHz, DMSO-d₆): δ10.06 (s, 1H), 9.30 (s, 1H), 7.85 (m, 3H), 1.86 (m, 4H), 0.55 (m, 6H).MS: m/z=219 [M+1]⁺.

Step 5: Preparation of3,3-diethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehydeoxime

To a mixture of3,3-diethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carb-aldehyde(1.1 g, 5.04 mmol) and NH₂OH.HCl (420 mg, 6.05 mmol) in THF (20 ml) andH₂O (5 ml) at rt was added NaOAc (578 mg, 7.06 mmol). The mixture wasstirred at rt for 16 h, diluted with H₂O and extracted with EA (20ml×2). The combined organic layers were washed with aqueous NaHCO₃ andbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography over silicagel eluted with PE:EA (10:1 to 1:1) to give the product (600 mg, yield51%) as white solid: MS: m/z=234 [M+1]⁺.

Step 6 and7:5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-diethylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution of3,3-diethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehydeoxime (251 mg, 1.07 mmol) in DMF (15 ml) at rt was added NCS (151 mg,1.13 mmol). The reaction mixture was warmed to 45° C., stirred for 1.5 hand cooled to −10° C. To this mixture was successively added1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (516 mg, 2.15mmol) and TEA (326.3 mg, 3.23 mmol) below −10° C. The mixture wasstirred at this temperature for 2 h, poured into ice-water and extractedwith EA (40 ml×2). The combined organic layers were washed with aqueousNaHCO₃ and brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatography oversilica gel eluted with PE:EA (10:1 to 5:1) to give the desired titlecompound5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-diethylbenzo[c][1,2]oxaborol-1(3H)-ol(180 mg, yield 35.5%) as white solid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.22(s, 1H), 7.85-7.45 (m, 6H), 4.48-4.22 (m, 2H), 2.00-1.70 (m, 4H),0.68-0.42 (m, 6H) ppm. MS: m/z=472 [M+1]⁺.

37.5-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1H-spiro[benzo[c][1,2]oxaborole-3,1′-cyclopentan]-1-ol

The title compound was prepared by using the same method as describedfor5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-diethyl-benzo[c][1,2]oxaborol-1(3H)-olwith cyclopentanone to replace 3-pentanone. It was obtained as a whitesolid. ¹H NMR (300 MHz, DMSO-d₆): δ 9.20 (s, 1H), 7.80 (t, J=1.8 Hz,1H), 7.72 (s, 3H), 7.61 (d, J=1.5 Hz, 2H), 4.44 (d, J=18.3 Hz, 1H), 4.31(d, J=18.3 Hz, 1H), 2.11-1.71 (m, 8H) ppm.

38.5-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1H-spiro[benzo[c]1,2]oxaborole-3,1′-cyclohexan]-1-ol

The title compound was prepared by using the same method as describedfor5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-diethyl-benzo[c][1,2]oxaborol-1(3H)-olwith cyclohexanone to replace 3-pentanone. It was obtained as a whitesolid. ¹H NMR (300 MHz, DMSO-d6): δ 9.22 (s, 1H), 7.82-7.61 (m, 6H),4.47-4.27 (m, 2H), 1.68-0.84 (m, 10H). MS: m/z=484 [M+1]⁺.

39.5-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4-fluoro-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of methyl 6-bromo-2-fluoro-3-methylbenzoic acid

To a solution of 4-bromo-2-fluoro-1-methylbenzene (21.9 g, 116 mmol) inTHF (100 mL) was added lithium diisopropylamide (LDA) (2 M solution inTHF, 69 mL, 139 mmol) at −78° C. After being stirred at −78° C. for 1 h,the reaction was treated with excess solid carbon dioxide, and stirredwhile the reaction temperature slowly rose to room temperature. Themixture was concentrated and then partitioned between 4N NaOH and ethylacetate. The aqueous phase was adjusted to pH 2 with 2N HCl and thenextracted three times with ethyl acetate. The combined extracts werewashed with water and brine, dried over with anhydrous Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified bycolumn chromatography on silica gel eluted with EA to give methyl6-bromo-2-fluoro-3-methylbenzoic acid (23.3 g, 86.2%) as a white solid.

Step 2: Preparation of methyl 6-bromo-2-fluoro-3-methylbenzoate

To a suspension of 6-bromo-2-fluoro-3-methylbenzoic acid (9.26 g, 39.74mmol) and K₂CO₃ (5.48 g, 39.74 mmol) in DMF (50 mL) was added dropwiseMeI (3.47 g, 59.61 mmol) at room temperature. The mixture was stirredfor 3 h until TLC analysis indicated the disappearance of the acid. Themixture was extracted three times with ethyl acetate. The combinedextracts were washed with water and brine, dried over with anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel eluted with PE-EA(20:1) to give 6-bromo-2-fluoro-3-methylbenzoate (9.3 g, 94.9%) as lightyellow oil. ¹H NMR (500 MHz, DMSO-d₆) δ 7.467 (d, J=8.0 Hz, 1H), 7.405(t, J=8.0 Hz, 1H), 3.910 (s, 3H), 2.229 (s, 3H) ppm.

Step 3: Preparation of 2-(6-bromo-2-fluoro-3-methylphenyl)propan-2-ol

To a solution of 6-bromo-2-fluoro-3-methylbenzoate (9.3 g, 37.65 mmol)in dry THF (100 mL) was added dropwise MeMgI (3M solution in ethylether, 50 mL, 150.6 mmol) at 0° C. under argon and then stirred at roomtemperature for 1 h. The reaction mixture was quenched with saturatedNH₄Cl and the mixture was extracted three times with ethyl acetate. Thecombined extracts were washed with water and brine, dried over withanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel eluted withPE-EA (10:1) to give 2-(6-bromo-2-fluoro-3-methylphenyl)propan-2-ol (2.7g, 29%) as a light yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 7.197 (d,J=8.0 Hz, 1H), 6.834 (t, J=8.0 Hz, 1H), 3.395 (s, 1H), 2.126 (s, 3H),1.675 (d, J=4.0 Hz, 6H) ppm.

Step 4: Preparation of1-bromo-2-(2-(ethoxymethoxy)propan-2-yl)-3-fluoro-4-methylbenzene

To a solution of 2-(6-bromo-2-fluoro-3-methylphenyl)propan-2-ol (2.15 g,8.7 mmol) in DIPEA (4 mL) was added (chloromethoxy)ethane (2.5 g, 26.1mmol). The reaction mixture was heated at 100° C. in a microware for 1h. Water (100 mL) was added and the mixture was extracted three timeswith ethyl acetate. The combined extracts were washed with water andbrine, dried over with anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by column chromatography onsilica gel eluted with PE-EA (10:1) to give2-(6-bromo-2-fluoro-3-methylphenyl)propan-2-ol (2.52 g, 95%) ascolorless oil. ¹H NMR (500 MHz, CDCl₃) δ 7.243 (d, J=8.0 Hz, 1H), 6.831(t, J=8.0 Hz, 1H), 4.592 (s, 2H), 3.556 (q, J=7.0 Hz, 2H), 2.113 (s,3H), 1.733 (d, J=5.5 Hz, 6H), 1.095 (t, J=7.0 Hz, 3H) ppm.

Step 5: Preparation of2-(2-(2-(ethoxymethoxy)propan-2-yl)-3-fluoro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of1-bromo-2-(2-(ethoxymethoxy)propan-2-yl)-3-fluoro-4-methylbenzene (4.48g, 14.7 mmol), bis(pinacolato)diboron (11.2 g, 44.2 mmol), Pd(dppf)Cl₂(539 mg, 0.7 mmol) and KOAc (4.33 g, 44.2 mmol) in 1,4-dioxane (60 mL)was stirred at 80° C. overnight under argon. Water (100 mL) was addedand the mixture was extracted three times with ethyl acetate. Thecombined extracts were washed with water and brine, dried over withanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel eluted withPE-EA (10:1) to give2-(2-(2-(ethoxymethoxy)propan-2-yl)-3-fluoro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneas a crude white solid.

Step 6: Preparation of4-fluoro-3,3,5-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution of the crude compound2-(2-(2-(ethoxymethoxy)propan-2-yl)-3-fluoro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(5.17 g, 14.7 mmol) in THF (147 mL) was added 6 N HCl (147 mL). Thereaction mixture was stirred at room temperature overnight, and theresulting mixture was extracted three times with ethyl acetate. Thecombined extracts were washed with water and brine, dried over withanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel eluted withPE-EA (10:1) to give4-fluoro-3,3,5-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol (1.52 g, 53.8%yield over 2 steps) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 7.339(d, J=7.5 Hz, 1H), 7.200 (t, J=6.5 Hz, 1H), 5.652 (s, 1H), 2.330 (s,3H), 1.642 (s, 6H) ppm.

Step 7: Preparation of4-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde

To a solution of 4-fluoro-3,3,5-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol(970 mg, 5 mmol) in CCl₄ (50 mL) at rt was added benzoyl peroxide (121mg, 0.5 mmol) followed by NBS (1.958 g, 11.0 mmol). The reaction mixturewas heated under reflux for 16 h, cooled to rt and treated with Na₂CO₃.The aqueous layer was acidified with 3 N HCl to pH 3 and extracted threetimes with ethyl acetate. The combined extracts were washed with waterand brine, dried over with anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel eluted with PE-EA (2:1) to give4-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde(688 mg, 68%) as a light yellow solid.

Step 8: Preparation of4-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehydeoxime

To a solution of4-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde(136 mg, 0.7 mmol) and NH₂OH.HCl (58.5 mg, 0.84 mmol) in THF (4 mL) andH₂O (1 mL) at rt was added NaOAc (80.5 mg, 0.98 mmol). The reactionmixture was stirred for 2 h and diluted with H₂O. The mixture wasextracted three times with ethyl acetate and the organic layer wasseparated. The organic solution was washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure to give crudecompound4-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehydeoxime as a light yellow solid. It was used in next step without furtherpurification.

Step 9: Preparation of4-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride

To a solution of the crude compound6-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehydeoxime (163 mg, 0.7 mmol) in DMF (4.0 mL) at rt was added NCS (111 mg,0.84 mmol). The reaction mixture was stirred at 40° C. for up to 2 h.The mixture was cooled to rt, poured into ice-water and extracted threetimes with ethyl acetate. The organic solution was washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure togive the crude compound4-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride as light yellow oil. It was used in next step without furtherpurification.

Step 10: Preparation of5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4-fluoro-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution of the crude compound4-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (180 mg. 0.70 mmol) and1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (203 mg, 0.84mmol) in DMF (5 mL) at rt was added TEA (117 μL, 0.84 mmol). Thereaction mixture was stirred for 12 h, poured into ice-water andextracted three times with ethyl acetate. The organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by prep-TLC eluted with PE-EA (3:2)and then purified by combiflash to give the title compound5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4-fluoro-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol[80 mg; yield 24.8% over the last 3 steps] as a white solid. ¹H NMR (500MHz, DMSO-d₆): δ 9.479 (s, 1H), 7.810 (t, J=1.5 Hz, 1H), 7.753 (t, J=7.5Hz, 1H), 7.671 (d, J=1.5 Hz, 2H), 7.582 (d, J=7.5 Hz, 1H), 4.376 (d,J=18.0 Hz, 1H), 4.270 (d, J=18.0 Hz, 1H), 1.55 (s, 6H) ppm; HPLC purity:100% at 220 nm and 100% at 254 nm; MS: m/z=462.0 (M+1, ESI+).

40.4-Fluoro-3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol

The title compound was synthesized by the following scheme:

Step 1: Preparation of4-fluoro-3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoro-methyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol

To a solution of the crude compound4-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (257 mg, 1 mmol) and1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (327 mg, 1.2mmol) in DMF (5 mL) at rt was added TEA (167 μL, 1.2 mmol). The reactionmixture was stirred for 12 h, poured into ice-water and extracted threetimes with ethyl acetate. The organic layer was washed with brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by prep-TLC eluted with PE-EA (3:2) and thenpurified by combiflash to give the title compound4-fluoro-3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol(80 mg; yield 16.1% over 3 steps from the aldehyde) as a white solid. ¹HNMR (500 MHz, DMSO-d₆): δ 9.461 (s, 1H), 7.891 (s, 2H), 7.754 (t, J=7.0Hz, 1H), 7.586 (d, J=7.5 Hz, 1H), 4.377 (d, J=18.5 Hz, 1H), 4.291 (d,J=18.5 Hz, 1H), 1.55 (s, 6H) ppm; HPLC purity: 100% at 220 nm and 100%at 254 nm; MS: m/z=496.0 (M+1, ESI+).

41.5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-6-fluoro-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

Step 1: Preparation of 4-fluoro-5-methyl-2-nitrobenzoic acid

To a solution of 4-fluoro-3-methylbenzoic acid (3.7 g, 24 mmol) in conc.H₂SO₄ (50 mL) at 0° C. was added KNO₃ (3.6 g, 36 mmol) in one portionand the mixture was stirred at rt for 2 h. The reaction mixture waspoured into ice water (200 mL) and extracted with DCM (100 mL×2). Theorganic layer was washed with brine, dried and concentrated to give thecrude 4-fluoro-5-methyl-2-nitrobenzoic acid (5 g) as white solid. It wasused in the next step without further purification.

Step 2: Preparation of methyl 4-fluoro-5-methyl-2-nitrobenzoate

To a solution of the crude 4-fluoro-5-methyl-2-nitrobenzoic acid (5 g)in MeOH (50 mL) was slowly added SOCl₂ (3.5 mL, 48 mmol) dropwise andthe resulting mixture was refluxed overnight. Then the solvent wasremoved to give crude methyl 4-fluoro-5-methyl-2-nitrobenzoate (5 g) asa white solid. It was used in the next step without furtherpurification.

Step 3: Preparation of methyl 2-amino-4-fluoro-5-methylbenzoate

The solution of crude methyl 4-fluoro-5-methyl-2-nitrobenzoate (5 g) inMeOH (50 mL) was hydrogenated using 10% Pd/C (0.5 g) as catalyst atatmospheric pressure overnight. The catalyst was removed by filtration,and the solvent was evaporated at reduced pressure. The residue waspurified by column chromatography on silica gel eluted with PE-EA (8:1)to give methyl 2-amino-4-fluoro-5-methylbenzoate (2.21 g, yield 50% overthree steps) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 7.715 (d, J=9.0Hz, 1H), 6.339 (d, J=11.5 Hz, 1H), 3.873 (s, 3H), 2.154 (s, 3H) ppm.

Step 4: Preparation of methyl 2-bromo-4-fluoro-5-methylbenzoate

To the suspension of methyl 2-amino-4-fluoro-5-methylbenzoate (2.2 g, 12mmol) in 48% hydrobromic acid (80 mL) was added an aqueous solution (32mL) of sodium nitrite (828 mg, 12 mmol) at 0° C., and the resultingsolution was stirred for 30 min. Copper (I) bromide (1.72 g, 12 mmol)was added to the solution at 0° C. and the resulting reaction mixturewas stirred at r.t for 1 h. After addition of ethyl acetate (200 mL),the reaction mixture was washed with water (200 mL×2), dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel eluted with PE-EA(10:1) to give methyl 2-bromo-4-fluoro-5-methylbenzoate (2.2 g, yield74%) as colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 7.655 (d, J=8.0 Hz,1H), 7.257 (d, J=8.5 Hz, 1H), 3.837 (s, 3H), 2.177 (s, 3H) ppm.

Step 5: Preparation of 2-(2-bromo-4-fluoro-5-methylphenyl)propan-2-ol

To a solution of methyl 2-bromo-4-fluoro-5-methylbenzoate (4.66 g, 18.87mmol) in dry THF (90 mL) was added dropwise MeMgI (31 mL, 94.33 mmol) at0° C. under argon and then stirred at rt for 16 h. The reaction mixturewas quenched with saturated NH₄Cl and extracted with EA (200 mL×2). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel eluted with PE-EA (20:1)to give 2-(2-bromo-4-fluoro-5-methylphenyl)propan-2-ol (3.24 g, 70%) ascolorless oil. ¹H NMR (500 MHz, CDCl₃) δ 7.427 (d, J=8.5 Hz, 1H), 7.189(d, J=11.0 Hz, 1H), 2.168 (s, 3H), 1.651 (s, 6H) ppm.

Step 6: Preparation of1-bromo-2-(2-(ethoxymethoxy)propan-2-yl)-5-fluoro-4-methylbenzene

To a solution of 2-(2-bromo-4-fluoro-5-methylphenyl)propan-2-ol (2.0 g,8.1 mmol) in DMF:DIPEA (2:1, 9 mL) was added (chloromethoxy)ethane (1.53g, 16.2 mmol). The reaction mixture was heated at 100° C. in microwareequipment for 1.5 h. Water (200 mL) was added and the mixture wasextracted with DCM (200 mL×2). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel eluted with PE-EA (30:1) to give1-bromo-2-(2-(ethoxymethoxy)propan-2-yl)-5-fluoro-4-methylbenzene (2.2g, 89%) as colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 7.208-7.234 (m, 2H),4.572 (s, 2H), 3.594 (q, J=7.0 Hz, 2H), 2.149 (s, 3H), 1.665 (s, 6H),1.115 (t, J=7.0 Hz, 3H) ppm.

Step 7: Preparation of2-(2-(2-(ethoxymethoxy)propan-2-yl)-5-fluoro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of1-bromo-2-(2-(ethoxymethoxy)propan-2-yl)-5-fluoro-4-methylbenzene (2.3g, 7.56 mmol), bis(pinacolato)diboron (2.1 g, 8.32 mmol), Pd(dppf)Cl₂(127 mg, 0.15 mmol) and KOAc (1.1 g, 11.34 mmol) in 1,4-dioxane (60 mL)was stirred at 80° C. overnight under argon. Water (200 mL) was addedand the mixture was extracted with DCM (200 mL×2). The combined organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel eluted with PE-EA (20:1) to give2-(2-(2-(ethoxymethoxy)propan-2-yl)-5-fluoro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxa-borolane(2.35 g, 88%) as a white solid.

Step 8: Preparation of6-fluoro-3,3,5-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution of2-(2-(2-(ethoxymethoxy)propan-2-yl)-5-fluoro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.35 g, 6.68 mmol) in THF (67 mL) was added 6 N HCl (67 mL). Thereaction mixture was stirred at room temperature overnight, andextracted with DCM (200 mL×2). The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel eluted with PE-EA (from 10:1 to 3:1) to give6-fluoro-3,3,5-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol (835 mg, 64%) asa white solid. ¹H NMR (500 MHz, CDCl₃) δ 7.189 (d, J=8.0 Hz, 1H), 6.995(d, J=6.5 Hz, 1H), 5.950 (s, 1H), 2.266 (s, 3H), 1.472 (s, 6H) ppm.

Step 9: Preparation of6-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]-oxaborole-5-carbaldehyde

To a solution of 6-fluoro-3,3,5-trimethylbenzo[c][1,2]oxaborol-1(3H)-ol(388 mg, 2 mmol) in CCl₄ (60 mL) at rt was added benzoyl peroxide (48.4mg, 0.2 mmol) followed by NBS (783 mg, 4.4 mmol). The reaction mixturewas heated under reflux for 16 h, cooled to rt and treated with Na₂CO₃.The aqueous layer was acidified with 3 N HCl to pH of 3 and extractedwith DCM (60 mL×3). The organic layer was dried over Na₂SO₄, filteredand concentrated under reduced pressure to give6-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde(378 mg, 91%) as a pale yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 10.369(s, 1H), 7.687 (d, J=5.5 Hz, 1H), 7.409 (d, J=8.0 Hz, 1H), 2.715 (s,3H), 1.484 (s, 6H) ppm.

Step 10: Preparation of6-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehydeoxime

To a solution of6-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde(200 mg, 0.96 mmol) and NH₂OH.HCl (79.5 mg, 1.15 mmol) in THF (4 mL) andH₂O (1 mL) at rt was added NaOAc (110 mg, 1.34 mmol). The reactionmixture was stirred for 2 h and diluted with H₂O. The mixture wasextracted with DCM (60 mL×3) and the organic layer was separated. Theorganic solution was washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give crude compound6-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehydeoxime as a light yellow solid. It was used in next step without furtherpurification.

Step 11: Preparation of6-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride

To a solution of the crude compound6-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehydeoxime (205 mg, 0.92 mmol) in DMF (4.0 mL) at rt was added NCS (147 mg,1.1 mmol). The reaction mixture was stirred at 45° C. for 3 h. Themixture was cooled to rt, poured into ice-water and extracted with DCM(60 mL×3). The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the crudecompound6-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride as colorless oil. It was used in next step without furtherpurification.

Step 12: Preparation of5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-6-fluoro-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol

To a solution of the crude compound6-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (300 mg, 0.92 mmol) and1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (222 mg, 0.92mmol) in DMF (5 mL) at rt was added TEA (152 μL, 1.1 mmol). The reactionmixture was stirred for 12 h, poured into ice-water and extracted withDCM (60 mL×3). The organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-TLC eluted with PE-EA (3:2) and then purified bycombiflash to give the title compound5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-6-fluoro-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol(108 mg; yield 29% over 3 steps) as a white solid. ¹H NMR (400 MHz,DMSO-d6): δ 9.379 (s, 1H), 7.815-7.848 (m, 2H), 7.660 (s, 2H), 7.513 (d,J=10.0 Hz, 1H), 4.401 (d, J=18.4 Hz, 1H), 4.254 (d, J=18.8 Hz, 1H),1.485 (s, 6H) ppm; HPLC purity: 100% at 220 nm and 100% at 254 nm; MS:m/z=462.0 (M+1, ESI+).

42.6-Fluoro-3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol

The title compound was synthesized by the following scheme:

Step 1: Preparation of6-fluoro-3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol

To a solution of the crude compound6-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoylchloride (310 mg, 0.95 mmol) and1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (262 mg, 0.95mmol) in DMF (5 mL) at rt was added TEA (158 μL, 1.2 mmol). The reactionmixture was stirred for 12 h, poured into ice-water and extracted withDCM (60 mL×3). The organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by prep-TLC eluted with PE-EA (3:2) and then purified bycombiflash to give the title compound6-fluoro-3,3-dimethyl-5-(5-(3,4,5-trichloro-phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol(86 mg; yield 16% over 3 steps from the aldehyde) as a white solid. ¹HNMR (500 MHz, DMSO-d₆): δ 9.352 (s, 1H), 7.875 (s, 2H), 7.826 (d, J=6.0Hz, 1H), 7.513 (d, J=10.0 Hz, 1H), 4.399 (d, J=18.5 Hz, 1H), 4.274 (d,J=18.5 Hz, 1H), 1.482 (s, 6H) ppm; HPLC purity: 100% at 220 nm and 100%at 254 nm; MS: m/z=495.9 (M+1, ESI+).

EXAMPLE 2 Activity of Various Compounds Against Larval-Stage Lone StarTicks (Amblyomma americanum) in a Larval Immersion Microassay

The larval immersion microassay was conducted as described in detail inWhite, et al., J. Med. Entomol. 41: 1034-1042 (2004). Compounds of theinvention were formulated in dimethylsulfoxide (DMSO) to prepare a stocksolution at a concentration of at least 10 mM. Using 96-well microtiterplates, an aliquot of the 10 mM sample was subsequently diluted in awater-based solution containing 1% ethanol and 0.2% Triton X-100, toobtain the desired concentration (typically 0.3 mM or lower) of compoundin a volume of 0.1 ml (minimum n=3 replicates per compound orconcentration). Approximately 30-50 Lone star tick larvae (Amblyommaamericanum) were submerged into each well containing compounds. After a30 minute immersion period, larvae were removed with a wide-bore pipettetip in 0.05 ml of fluid, dispensed into a commercial paper tissue biopsybag which was sealed at the top with a plastic dialysis clip, invertedand allowed to air dry for 60 minutes. Bags containing larvae were thenincubated at approximately 27 degrees Celsius and >90% relativehumidity. After 24 hours, bags were opened, live and dead larvae werecounted and percent larval mortality was calculated.

The following compounds exhibited ≧80% activity when tested in thisassay at a concentration of no greater than 0.3 mM: 1, 2, 3, 5, 6, 7, 8,9, 10, 11, 12, 14, 17, 19, 21, 22, 23, 24, 25, 26, 27, 28, 30, 32, 34,35, 41, 42.

EXAMPLE 3 Efficacy of Various Compounds Against Nymphal-Stage AmericanDog Ticks (Dermacentor variabilis) on Rats

Evaluations were conducted using a modified version of the assay asdescribed in Gutierrez et al., J. Med. Entomol. 43(3): 526-532 (2006).This assay may be modified by simply using different tick species (thereference describes Amblyomma americanum ticks), such as Dermacentorvariabilis or Rhipicephalus sanguineus ticks, as well as differentlife-stages (larval, nymphal or adult). Further, the reference describesusing topical application methods, but oral, transdermal andsubcutaneous injection routes of administration may be used.

In these studies, adult male or female rats, approximately 300 grams insize, were randomly assigned to a treatment group or a control(untreated negative control or fipronil positive control) group. Eachgroup consisted of three (3) to five (5) rats. One day before treatment(Day −1), rats were infested with approximately ten (10) D. variabilistick nymphs, which were allowed to attach and begin feeding for 24hours. On Day 0, rats in treated groups were orally administeredcompounds dissolved in polyethylene glycol-300, propylene glycol andwater, at point dosages of 5-25 mg/kg bodyweight. Fipronil was preparedin similar fashion and administered orally at 10 mg/kg bodyweight. OnDay 2, approximately forty-eight (48) hours after treatment, live anddead ticks were removed from animals and counted.

Live tick counts were transformed using the natural logarithmtransformation plus one (Ln count+1); addition of one to each countserved to adjust for counts that were zero. Geometric mean (GM) grouptick counts were obtained via back-transformation of group meantransformed counts and subtracting one. The contemporaneous negativecontrol group was used for comparison to the compound treatment groupsfor the calculation of percent efficacy (% reduction in live tickcounts). GM percent efficacy of treatments was calculated using thefollowing formula:

${\% \mspace{14mu} {Efficacy}} = {\frac{A - B}{A} \times 100}$

-   -   A=GM No. Live Ticks Control; B=GM No. Live Ticks Treated

Efficacy results are illustrated in Table 1. Fipronil yielded >95%efficacy in all studies. No abnormal clinical signs or adverse effectsattributable to test compounds were noted during any of the studies.

TABLE 1 Maximum in vivo efficacy obtained against Dermacentor variabilisticks on rats for compounds administered orally at a point dose ofbetween 5-25 mg/kg body weight. Compounds Compounds exhibitingexhibiting 40% ≦ Compounds exhibiting efficacy < 40% efficacy < 80%efficacy ≧ 80% 4 (0.0%), 9 (0.0%), 30 (41.3%) 28 (>80%); 14 (83.5%), 15(0.0%), 18 (0.0%), 31 (88.0%), 24 (95.6%), 22 (0.0%), 29 (0.0%) 3(97.9%), 2 (100%), 33 (0.0%), 36 (0.0%), 5 (100%), 6 (100%), 37 (0.0%),38 (0.0%), 7 (100%), 8 (100%), 39 (0.0%), 40 (0.0%), 10 (100%), 11(100%), 41 (0.0%), 42 (0.0%), 17 (100%), 19 (100%), 13 (7.1%), 16(19.1%), 21 (100%), 23 (100%), 1 (21.8%), 12 (25.0%), 25 (100%), 26(100%), 34 (25.5%), 20 (28.0%) 27 (100%), 32 (100%) 35 (100%)

EXAMPLE 4 Efficacy of 7 Against Adult American Dog Tick (Dermacentorvariabilis) and Cat Flea (Ctenocephalides felis) Infestations on Dogs

The therapeutic (knockdown) and residual efficacy of 7, administeredorally at a point dosages of 5 and 25 mg/kg bodyweight, was evaluatedagainst adult American dog tick (D. variabilis) and cat flea (C. felis)infestations on dogs. Sixteen (16) male and female beagle dogs wereallocated to one of four treatment groups: Untreated control group (n=4dogs); 7, 5 mg/kg liquid oral dosage form (n=4 dogs); 7, 25 mg/kg liquidoral dosage form (n=4 dogs); and 7, 25 mg/kg solid oral dosage form.Liquid dosage forms were prepared by dissolving 7 in a solution of 55%polyethylene glycol-300, 35% propylene glycol and 10% water at 25 mg/ml.Solid oral dosage form was prepared by thoroughly mixing 7 withmicrocrystalline cellulose and croscarmellose sodium (50:47:3, w/w) andplacing into size 00 gelatin capsules. On Day 0, all dogs were orallyadministered 7 at the prescribed point dosages. Twenty-four (24) hoursbefore treatment (Day −1), all dogs were infested with approximately 50unfed, adult-stage American dog ticks (D. variabilis; approximately 50%male and 50% female). On Day 2, approximately 48 hours after treatment,ticks were removed and counts were conducted to determine the number andlife-status classification of ticks present on all dogs (normal,moribund or dead; attached or detached). For all groups, dogs werere-infested with approximately 50 unfed, adult D. variabilis ticks onDays 5 and 12, with tick classification, counts and removal on Days 7and 14 (approximately 48 hours after each infestation). For negativecontrol and 7 (25 mg/kg solid oral dosage form) groups, dogs werere-infested with approximately 50 unfed, adult D. variabilis ticks onDays 19 and 28, with tick classification, counts and removal on Days 21and 30 Immediately following removal of ticks on Day 30, dogs in thenegative control and 7 (25 mg/kg solid oral dosage form) groups wereinfested with approximately 100 unfed, adult cat fleas (C. felis). Fleacounts were conducted approximately 48 hours later, on Day 32.

The total number of live ticks or fleas (normal plus moribundclassification) present on each dog was determined for each interval,and this number was transformed using the natural logarithmtransformation plus one (Ln count+1); addition of one to each countserved to adjust for counts that were zero. Geometric mean (GM) grouptick or flea counts were obtained via back-transformation of group meantransformed counts and subtracting one. The negative control group wasused for comparison to 7 groups for the calculation of percent efficacy(% reduction in live tick or flea counts). GM percent efficacy oftreatments was calculated using the following formula:

${\% \mspace{14mu} {Efficacy}} = {\frac{A - B}{A} \times 100}$

-   -   A=GM No. Live Ticks or Fleas Control; B=GM No. Live Ticks or        Fleas Treated

Efficacy results are illustrated in Table 2. Both oral dosage forms at25 mg/kg provided 100% therapeutic efficacy at 24 hour and 48 hourpost-treatment time points against adult D. variabilis ticks. Residualefficacy was 93% and 98% on Day 7 for 25 mg/kg liquid and 25 mg/kg solidoral dosage form groups, respectively. By Day 14, efficacy of the 25mg/kg solid oral dosage form was superior to the 25 mg/kg liquid oraldosage form (82% versus 52%). Residual tick efficacy of the 25 mg/kgsolid oral dosage form was 74% at Day 21 and 62% at Day 30. Thetherapeutic and residual efficacy of the 5 mg/kg liquid oral dosage formwas <70% at all intervals.

Activity against fleas was >95% with the 25 mg/kg solid oral dosage formon Day 32. Treatment with 7 was well tolerated by both dogs.

TABLE 2 Geometric mean group live parasite counts (% efficacy) for 7,administered orally at 5 or 25 mg/kg bodyweight in liquid or solid oraldosage form, against tick (Dermacentor variabilis) and cat flea(Ctenocephalides felis) infestations on dogs. D. variabilis C. felisTreatment Day Day Day Day Group Day 2 Day 7 14 21 30 32 Negative 33.135.5 35.2 26.3 28.4 80.1 Control (—) (—) (—) (—) (—) (—) 7 10.6  36.536.8 nd* nd nd 5 mg/kg (68.2)   (0.0)  (0.0) (liquid) 7 0.0  2.6 16.9 ndnd nd 25 mg/kg (100)    (92.8) (52.1) (liquid) 7 0.0  0.7  6.3  6.8 10.7 3.9 25 mg/kg (100)    (98.1) (82.2) (74.2) (62.2) (95.2) (solid) *nd,denotes not determined.

EXAMPLE 5 Efficacy of 7 and 8, Administered Orally at 25 mg/Kg or 50mg/Kg, Against Adult American Dog Tick (Dermacentor variabilis) andBrown Dog Tick (Rhipicephalus sanguineus) Infestations on Dogs

The therapeutic (knockdown) and residual efficacy of 7 and 8, eachadministered orally at a point dose of either 25 mg/kg or 50 mg/kgbodyweight, was evaluated against adult tick (Dermacentor variabilis andRhipicephalus sanguineus) infestations on dogs. Twenty (20) male andfemale beagle dogs were allocated to one of five treatment groups, four(4) dogs per group: Untreated control; 7, 25 mg/kg; 7, 50 mg/kg; 8, 25mg/kg; and 8, 50 mg/kg. On Day −1, all dogs were infested withapproximately 50 unfed, adult D. variabilis ticks. On Day 0, dogs wereorally administered gelatin capsules containing either 7 or 8 (50%technical active, 47% microcrystalline cellulose and 3% croscarmellosesodium, w/w) so as to achieve the desired point dosages. Ticks werecounted and classified on all dogs, but not removed, on Day 1(approximately 24 hours after treatment). On Day 2, approximately 48hours after treatment, ticks were counted, classified and removed. Dogswere re-infested with the same number of D. variabilis ticks on Days 5,12 and 19 with corresponding 48 hour post-infestation tick counts onDays 7, 14 and 21. Dogs were infested with approximately 50 unfed, adultbrown dog ticks (Rhipicephalus sanguineus; approximately 50% male and50% female) on Days 15 and 28, with corresponding 48 hourpost-infestation tick counts on Days 17 and 30. GM percent efficacy oftreatments against both tick species was calculated using the followingformula:

${\% \mspace{14mu} {Efficacy}} = {\frac{A - B}{A} \times 100}$

-   -   A=GM No. Live Ticks or Fleas Control; B=GM No. Live Ticks or        Fleas Treated

Efficacy results are illustrated in Table 3. 7 and 8 yielded 100%therapeutic efficacy within 48 hours of treatment at both 25 and 50mg/kg. Residual efficacy against D. variabilis ticks remained >90% forboth compounds at both doses through Day 7 and declined thereafter. Theresidual efficacy of 7 at 50 mg/kg was high, 94% against a R. sanguineusinfestation conducted between weeks 2 and 3. 7 and 8 were well toleratedby all dogs.

TABLE 3 Geometric mean group live tick counts (% efficacy) for 7 and 8,administered orally at point dosages of 25 or 50 mg/kg, against tick(Dermacentor variabilis and Rhipicephalus sanguineus) infestations ondogs. D. variabilis R. sanguineus Day Day Day Day Treatment Group Day 1Day 2 Day 7 14 21 17 30 Negative 10.5 10.0  22.9 16.5 16.2 27.1 37.1Control (—) (—) (—) (—) (—) (—) (—) 7 1.0 0.0 0.7 5.3 4.7 8.0 nd* 25mg/kg (90.4) (100)    (97.0) (67.6) (71.1) (75.0) 7 1.8 0.0 0.4 1.9 3.21.6 13.4 50 mg/kg (83.0) (100)    (98.2) (88.5) (80.1) (94.0) (63.9) 82.0 0.0 1.5 2.5 3.4 7.2 nd 25 mg/kg (81.0) (100)    (93.4) (85.0) (79.3)(73.4) 8 2.0 0.0 0.6 3.2 4.0 5.4 21.5 50 mg/kg (80.9) (100)    (97.5)(80.4) (75.1) (80.2) (42.1) *nd, denotes not determined.

EXAMPLE 6 Efficacy of 7, Administered Orally at 25 mg/Kg, Against AdultAmerican Dug Tick (Dermacentor variabilis) Infestations on Dogs

The efficacy of 7, administered orally at a point dose of 25 mg/kgbodyweight, was evaluated against adult tick (Dermacentor variabilis)infestations. Twelve (12) male and female beagle dogs were allocated tothree treatment groups: Untreated, negative control A; 7 group B; and 7group C (n=4 dogs per group). Dogs were infested with approximately 50unfed, adult D. variabilis ticks on Days −1, 5, 12, 19 and 28. For 7group B dogs, tick counts and classification were conducted at 48 hourpost-treatment or post-infestation intervals on Days 2, 7, 14, 21 and30. For negative control group A and 7 group C dogs, tick counts andclassification were conducted at 72 hour post-treatment orpost-infestation intervals on Days 3, 8, 15, 22 and 31. On Day 0, dogsin groups B and C were orally administered gelatin capsules containing 7(50% technical active, 47% microcrystalline cellulose and 3%croscarmellose sodium, w/w) at a point dose of 50 mg/kg. Both 48 hourand 72 hour counts in the treated groups were adjusted to counts fromthe same 72 hour negative control group. GM percent efficacy oftreatments was calculated using the following formula:

${\% \mspace{14mu} {Efficacy}} = {\frac{A - B}{A} \times 100}$

-   -   A=GM No. Live Ticks Control; B=GM No. Live Ticks Treated

Efficacy results are illustrated in Table 4. Therapeutic (knockdown)activity of 7, when administered orally at 50 mg/kg, was 99% within 48hours of treatment and 100% at 72 hours. Residual efficacy at 48 hourintervals was <90% through week 4 (Day 30), but was >99% using 72 hourcount intervals through week 3 (Day 22) and 97% at week 4 (Day 31). Asubstantial number of moribund ticks was observed on 7 group B dogs at48 hour intervals and was responsible for observed decline in residualefficacy for this group. Very few moribund ticks were observed on 7group C dogs at the 72 hour intervals, contributing to very goodresidual efficacy. Treatments were well tolerated by all dogs.

TABLE 4 Geometric mean group live tick counts (% efficacy) of 7,administered orally at 50 mg/kg bodyweight, against American dog tick(Dermacentor variabilis) infestations on dogs. D. variabilis Week 0 Week1 Week 2 Week 3 Week 4 48 h 72 h 48 h 72 h 48 h 72 h 48 h 72 h 48 h 72 hNegative 21.6 17.3 28.1 12.3 25.3 Control* (—) (—) (—) (—) (—) 7, 50mg/kg 0.3 0.0 2.6 0.0 6.1 0.2 10.7 0.0 16.3 0.8 (98.5) (100)    (85.1)(100)    (78.3) (99.3) (13.0) (100)    (35.5) (96.9) *Same control group(72 h) counts were used for comparison to 48 h and 72 h treated groupcounts.

EXAMPLE 7 Therapeutic Efficacy and Speed of Kill for 7, AdministeredOrally at 25 mg/Kg, Against Adult Cat Flea (Ctenocephalides felis)Infestations on Dogs

The therapeutic efficacy and speed of kill of 7, administered orally ata point dose of 25 mg/kg bodyweight, was evaluated against adult catflea (Ctenocephalides felts) infestations on dogs. Twelve (12) male andfemale beagle dogs were allocated to one of four treatment groups (n=3dogs per group). Group A was untreated, negative control; groups B, Cand D received 7. On Day −1, all dogs were infested with approximately100 unfed, adult fleas (approximately 50% male and 50% female). On Day0, dogs in groups B, C and D were orally administered gelatin capsulescontaining 7, at a point dose of 25 mg/kg (50% technical active, 47%microcrystalline cellulose and 3% croscarmellose sodium, w/w). At eight(8) hours post-treatment, fleas were counted and removed from dogs ingroup B; at twelve (12) hours post-treatment, fleas were counted andremoved from dogs in group C; and at twenty-four (24) hourspost-treatment, fleas were counted and removed from dogs in groups A andD. GM percent efficacy of treatments against fleas was calculated usingthe following formula:

${\% \mspace{14mu} {Efficacy}} = {\frac{A - B}{A} \times 100}$

-   -   A=GM No. Live Fleas Control; B=GM No. Live Fleas Treated

Efficacy results are illustrated in Table 5. 7 provided rapid knockdownagainst an existing flea infestation on dogs within twelve (12) hours oftreatment, and 100% efficacy within twenty-four (24) hours of treatment.Treatments were well tolerated by dogs.

TABLE 5 Geometric mean group live flea counts (% efficacy) of 7,administered orally at 25 mg/kg bodyweight, against cat flea (C. felis)infestations on dogs at the indicated post-treatment interval. TreatmentPost-Treatment Interval Group 8 hours 12 hours 24 hours Negative 85.7Control* (—) 7 75.6 0.3 0.0 25 mg/kg (11.8) (99.7) (100) *7 counts atall intervals were adjusted to the same count conducted on negativecontrol dogs at 24 hours post-treatment.

EXAMPLE 8 Biological Characterization and Comparison of the R and SEnantiomers of 7

7 contains one chiral center, and is therefore a racemic mixturecomprised of approximately 50% R- and 50% S-enantiomer. In vitro andsurrogate animal (rat) studies were conducted to evaluate the biologicalactivity of the R- and S-enantiomers of 7. For the in vitro study,larvae of the Lone star tick (Amblyomma americanum) were exposed to 17(S-enantiomer) and 18 (R-enantiomer) using the larval immersionmicroassay at a concentration of no greater than 0.3 mM. Followingexposure, larvae were removed, transferred to a tissue biopsy bag andincubated at approximately 27 degrees Celsius and >90% relativehumidity. After 24 hours, biopsy bags were opened and the numbers oflive and dead larvae were determined.

Enantiomers were evaluated for activity against American dog tick(Dermacentor variabilis) nymphs on rats. One day before treatment (Day−1), treated and negative control rats (n=3 to 5 rats per group) wereinfested with approximately ten (10) D. variabilis tick nymphs, whichwere allowed to attach and begin feeding for 24 hours. On Day 0, rats intreated groups were orally administered compounds dissolved inpolyethylene glycol-300, propylene glycol and water, at point dosages ofno greater than 5 mg/kg bodyweight. Fipronil was prepared in similarfashion and administered orally at 10 mg/kg bodyweight. On Day 2,approximately forty-eight (48) hours after treatment, live and deadticks were removed from animals and counted. GM percent efficacy oftreatments was calculated using the following formula:

${\% \mspace{14mu} {Efficacy}} = {\frac{A - B}{A} \times 100}$

-   -   A=GM No. Live Ticks Control; B=GM No. Live Ticks Treated

Enantiomer activity profiles are illustrated in Table 6. R-enantiomer 18was inactive (0.0%) against Amblyomma americanum larvae in the in vitrolarval immersion microassay at a concentration of 0.3 mM, whereasS-enantiomer 17 yielded ≧80% activity at a concentration of 0.3 mM. Whenadministered orally to D. variabilis nymph infested rats at point dosesof ≦5 mg/kg, 18 was inactive (10.7% tick reduction) whereas 17 wasactive (≧80% tick reduction). Treatment with both enantiomers was welltolerated by all rats.

TABLE 6 In vitro and in vivo comparative activity of R and S enantiomersagainst tick larvae and nymphs. Compound In vitro activity % Efficacy atID Enantiomer at 0.3 mM Dose of ≦5 mg/kg Racemate Parent 7 17 S 100%≧80% 18 R  0.0% 10.7%

Efficacy of 17, Administered Orally at 50 mg/Kg, Against Adult AmericanDog Tick (Dermacentor variabilis), Brown Dog Tick (Rhipicephalussanguineus) and Cat Flea (Ctenocephalides felis) Infestations on Dogs

The therapeutic (knockdown) and residual efficacy of 17, administeredorally at a point dose of 50 mg/kg bodyweight, was evaluated againstadult tick (Dermacentor variabilis and Rhipicephalus sanguineus) andadult cat flea (Ctenocephalides felis) infestations on dogs. Eight (8)male and female beagle dogs were allocated to either an untreated,negative control group or 17 group (n=4 dogs per group). Dogs wereinfested with approximately 50 unfed, adult D. variabilis ticks on Days−1, 5, 12, 19, and 28. On Day 0, dogs were orally administered gelatincapsules containing 17 (50% technical active, 47% microcrystallinecellulose and 3% croscarmellose sodium, w/w) at a point dose of 50mg/kg. D. variabilis tick counts and classification were conducted onDay 1 (thumb count, approximately 24 hours after treatment) and Days 2,7, 14, 21 and 30 (approximately 48 hours after treatment). Followingremoval of D. variabilis ticks on Day 30, all dogs were co-infested withapproximately 50 unfed, adult brown dog ticks (R. sanguineus) andapproximately 100 unfed, adult cat fleas (C. felis). Brown dog tick andcat flea counts were conducted on Day 32 (approximately 48 hours afterinfestation). GM percent efficacy of treatments against both tickspecies and fleas was calculated using the following formula:

${\% \mspace{14mu} {Efficacy}} = {\frac{A - B}{A} \times 100}$

A=GM No. Live Ticks or Fleas Control; B=GM No. Live Ticks or FleasTreated

Efficacy results are illustrated in Table 7. Against D. variabilis, 17demonstrated 98% knockdown within 24 hours of treatment; 100% within 48hours treatment; excellent residual efficacy of 97-100% through Day 21and 95% on Day 30. On Day 32, 17 yielded 94% efficacy against R.sanguineus ticks and 100% control of fleas. Oral treatment with 17 waswell tolerated by all dogs.

TABLE 7 Geometric mean group live parasite counts (% efficacy) of 17administered orally at 50 mg/kg bodyweight, against tick (Dermacentorvariabilis and Rhipicephalus sanguineus) and cat flea (Ctenocephalidesfelis) infestations on dogs. D. variabilis Treatment Day Day Day R.sanguineus C. felis Group Day 1 Day 2 Day 7 14 21 30 Day 32 Day 32Negative 28.4 33.8  30.6  36.9 36.2  39.4 32.3 59.2  Control (—) (—) (—)(—) (—) (—) (—) (—) 17  0.7 0.0 0.0  1.2 0.0  1.9  1.9 0.0 50 mg/kg(97.6) (100)    (100)    (96.7) (100)    (95.3) (94.1) (100)   

It is to be understood that the invention covers all combinations ofaspects with all other suitable aspects and/or exemplary embodimentsdescribed herein. It is to be understood that the invention also coversall combinations of exemplary embodiments with all other suitableaspects and/or exemplary embodiments described herein.

What is claimed is: 1.-20. (canceled)
 21. A method of treating a diseasein an animal comprising: contacting the animal with a compound having astructure of formula (I):

wherein Y is hydrogen, fluoro, chloro, or bromo; R¹ is phenylsubstituted 2-4 times, said substitutions comprising i) 1-4substitutions with the same or different of halo, and 0-1 substitutionswith methyl, difluoromethyl, trifluoromethyl, methoxy, trifluormethoxy,or trifluoroethoxy, or ii) 2 trifluoromethyl groups; R² is methyl,fluoromethyl, trifluoromethyl, or perfluoroethyl; R^(3a) and R^(3b) areindependently selected from hydrogen, methyl, ethyl, or fluoromethyl, orR^(3a) and R^(3b) combine with the carbon to which they are attached toform a cyclopentyl ring or a cyclohexyl ring wherein the animal is inneed of treatment thereof; or a salt thereof.
 22. The method of claim21, wherein the compound has a structure which is:

wherein C* is a carbon atom which is a stereocenter having a (S)configuration.
 23. The method of claim 21, wherein the compound has astructure which is:

wherein R^(1b), R^(1c), and R^(1d) are each independently selected fromhydrogen, fluoro, chloro, bromo, methyl, difluoromethyl,trifluoromethyl, methoxy, trifluormethoxy, or trifluoroethoxy, andR^(3a) and R^(3b) are the same and selected from methyl or fluoromethyl.24. The method of claim 21, wherein the compound has a structure whichis:

wherein R² is trifluoromethyl; and R^(1b), R^(1c), and R^(1d) are eachindependently selected from hydrogen, fluoro, chloro, or bromo.
 25. Themethod of claim 24, wherein R^(1b) is fluoro, chloro, or bromo; R^(1c)is hydrogen, fluoro, or chloro; and R^(1d) is fluoro, chloro, or bromo.26. The method of claim 21, wherein the compound is selected from5-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol;(S)-5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;(R)-5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3,5-Dibromophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3-Chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;3,3-Dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3,5-Dichloro-4-methylphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3,5-Dichloro-4-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3,5-Dichloro-4-(difluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3,5-Dichloro-4-(trifluoromethoxy)phenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3,5-Dichlorophenyl)-5-(perfluoroethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3,5-Bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3,5-Dichloro-4-(2,2,2-trifluoroethoxyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;3,3-Dimethyl-5-(5-methyl-5-(3,4,5-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol;(S)-3,3-Dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol;(R)-3,3-Dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3-Chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(Fluoromethyl)-5-(3,4,5-trichlorophenyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(4-Bromo-3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3,5-Dichloro-4-methoxyphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3,4-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(4-Fluoro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3-Chloro-4,5-difluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3,4-Dichloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3,5-Dibromo-4-chlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;(S)-5-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;(R)-5-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(4-Chloro-3,5-difluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;3,3-Dimethyl-5-(5-(trifluoromethyl)-5-(3,4,5-trifluorophenyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3,5-Dibromo-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;3,3-Bis(fluoromethyl)-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol;3,3-Dimethyl-5-(5-(2,3,4,5-tetrachlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3,5-Dichloro-2,4-difluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-diethyl-benzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1H-spiro[benzo[c][1,2]oxaborole-3,1′-cyclopentan]-1-01;5-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-1H-spiro[benzo[c][1,2]oxaborole-3,1′-cyclohexan]-1-ol;5-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4-fluoro-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;4-Fluoro-3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol;5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-6-fluoro-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol;or6-Fluoro-3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol,or a salt thereof.
 27. The method of claim 21, wherein the compound, ora salt thereof, is(R)-3,3-Dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol.28. The method of claim 21, wherein the compound, or a salt thereof, is3,3-Dimethyl-5-(5-(2,3,4,5-tetrachlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol.29. The method of claim 21, wherein the compound, or a salt thereof, ispart of a formulation also comprising at least one pharmaceuticallyacceptable excipient.
 30. The method of claim 21, wherein the disease isrosacea.
 31. The method of claim 21, wherein the animal is a human.